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Kawano M, Oshima Y, Shiratori F, Suzuki T, Yajima S, Funahashi K, Shimada H. Association of Circulating Basophil Count with Gastric Cancer Prognosis. J Gastrointest Cancer 2025; 56:54. [PMID: 39869243 DOI: 10.1007/s12029-025-01171-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 01/28/2025]
Abstract
PURPOSE Basophils play a crucial role in immunoglobulin E-mediated allergic reactions and parasitic infections. Recently, a low basophil count was reported to be a poor prognostic indicator in patients with malignant tumors. This study aimed to investigate the cut-off value to evaluate the clinicopathological and prognostic significance of the basophil count in patients with gastric cancer. METHODS This study enrolled 1192 gastric cancer patient who underwent surgery without preoperative chemotherapy between 2001 and 2020. The cutoff value was 26/μl based on the receiver of characteristics curves for overall survival, and 606 patients were classified as the low basophil group. The clinicopathological and prognostic significance of the low basophil count was assessed by univariate and multivariate analyses. RESULTS Elderly age (p < 0.001), high C-reactive protein level (p < 0.001), low lymphocyte count (p = 0.044), and low neutrophil count (p < 0.001) are independently associated with low basophil count. The low basophil group demonstrated a significantly worse overall survival than the high basophil group (p = 0.005). Although there was no significant difference in stage I, the low basophil group demonstrated poor overall survival in stage II/III/IV. In stage II, low basophil count was independently associated with poor OS. In stage III/IV, low basophil group tended to have poor overall survival rate. Including all stages, low basophil count was an independent risk factor for poor overall survival (hazard ratio (HR) = 1.29, 95% CI: 1.03-1.61, p = 0.027). CONCLUSION Low basophil count was significantly associated with elderly age, high C-reactive protein level, and low neutrophil count (<26/μl). In addition, low basophil count was an independent poor prognostic factor in patients with gastric cancer. Thus, preoperative circulating basophil count assessment may be useful for predicting the postoperative survival of patients with gastric cancer.
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Affiliation(s)
- Makiko Kawano
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
| | - Yoko Oshima
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan.
| | - Fumiaki Shiratori
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
| | - Takashi Suzuki
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
| | - Satoshi Yajima
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
| | - Kimihiko Funahashi
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
| | - Hideaki Shimada
- Department of Gastroenterological Surgery, Toho University Medical Center Omori Hospital, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 142-8541, Japan
- Department of Gastroenterological Surgery and Clinical Oncology, Graduate School of Medicine, Toho University, Tokyo, Japan
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Popęda M, Żok J, Tomasik B, Duchnowska R, Bieńkowski M. Complete blood counts as potential risk factors of early dissemination to liver and lungs in resected colorectal cancer: a retrospective cohort study. Int J Colorectal Dis 2025; 40:21. [PMID: 39836241 PMCID: PMC11750913 DOI: 10.1007/s00384-024-04802-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/30/2024] [Indexed: 01/22/2025]
Abstract
PURPOSE Liver and lung metastases demonstrate distinct biological, particularly immunological, characteristics. We investigated whether preoperative complete blood count (CBC) parameters, which may reflect the immune system condition, predict early dissemination to the liver and lungs in colorectal cancer (CRC). METHODS In this retrospective single-centre study, we included 268 resected CRC cases with complete 2-year follow-up and analysed preoperative CBC for association with early liver or lung metastasis development. Next, selected CBC and clinicopathological parameters were analysed with uni- and multivariable Cox regression. Independent factors affecting liver or lung metastasis-free survival were incorporated into composite scores, which were further evaluated with receiver operating characteristic (ROC) curves and dichotomised using a modified, specificity-focused, Youden approach to identify particularly high-risk patients. RESULTS Compared to metastasis-free patients, early liver metastases were related to decreases in red blood cells, haematocrit, lymphocytes and elevated monocyte-to-lymphocyte ratio, while lung metastases to lower eosinophil counts. A composite score of independent factors (erythrocytopenia, lower lymphocyte count and pN) yielded HR of 8.01 (95% CI 3.45-18.57, p < 0.001) for liver-specific metastasis-free survival (MFS). For lung-specific MFS, the combination of eosinopenia, pN and primary tumour location showed HR of 13.69 (95% CI 4.34-43.20, p < 0.001). CONCLUSION Early CRC metastases to the liver and lungs are associated with partially divergent clinicopathological and peripheral blood features. We propose simple, clinically implementable scores, based on routinely assessed parameters, to identify patients with an increased risk of early dissemination to the liver or lungs. After validation in independent cohorts, these scores may provide easily available prognostic information.
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Affiliation(s)
- Marta Popęda
- Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland.
| | - Jolanta Żok
- Department of Oncology, Military Institute of Medicine, Warsaw, Poland
| | - Bartłomiej Tomasik
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Renata Duchnowska
- Department of Oncology, Military Institute of Medicine, Warsaw, Poland
| | - Michał Bieńkowski
- Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland
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Zhan Z, Huang Z, Xie Z, Zhou H, Luo Y, Chen P, Luo T, Sun B, Cheng ZJ. Role of eosinophil counts in mediating the association between asthma and colon cancer. Clin Transl Allergy 2024; 14:e70012. [PMID: 39659035 PMCID: PMC11632118 DOI: 10.1002/clt2.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 09/07/2024] [Accepted: 11/24/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Epidemiological findings regarding the association between asthma and the risk of colon cancer (CC) are inconsistent. The causality and potential molecular mechanisms underlying asthma, eosinophil count, and CC remain unknown. METHODS We performed Mendelian randomization (MR) analysis to investigate the causality between asthma and CC and attempted to demonstrate that asthma indirectly affects CC mediated by eosinophil count through mediation analysis. Sensitivity analyses and multivariable MR were performed to test the robustness of our findings. Multiple bioinformatics tools were applied to further investigate the underlying mechanisms related to eosinophils that contribute to the pathogenesis of both asthma and CC. RESULTS MR with mediation analyses suggested that eosinophil count may play a role in the mechanism through which asthma reduces the risk of CC. Our bioinformatic analyses identified PPP1R14A as a potential therapeutic target and an eosinophil-associated biomarker for CC patients. Higher expression of PPP1R14A may be associated with a poorer prognosis in CC patients. Additionally, the lysosome pathway emerges as a shared eosinophil-related pathway in both asthma and CC. CONCLUSIONS Eosinophils may contribute to a lower risk of CC in patients with asthma. PPP1R14A is a potential therapeutic target and biomarker for CC.
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Affiliation(s)
- Zhi‐Qing Zhan
- Department of Clinical LaboratoryNational Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseaseState Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina
- Division of Gastroenterology and HepatologyShanghai Institute of Digestive DiseaseNHC Key Laboratory of Digestive DiseasesState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ze‐Min Huang
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Zhi‐Xin Xie
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Hao‐Bin Zhou
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Yu‐Hua Luo
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Pei‐Zhen Chen
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Tian‐Ye Luo
- Department of Clinical MedicineGuangzhou Medical UniversityGuangzhouChina
| | - Baoqing Sun
- Department of Clinical LaboratoryNational Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseaseState Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina
| | - Zhangkai J. Cheng
- Department of Clinical LaboratoryNational Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseaseState Key Laboratory of Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina
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Liang J, Zhou X, Lin Y, Yin H, Liu Y, Xie Z, Lin H, Wu T, Zhang X, Tan Z, Cheng Z, Yin W, Guo Z, Chen W. Prospective study on the association between 36 human blood cell traits and pan-cancer outcomes: a mendelian randomization analysis. BMC Cancer 2024; 24:1442. [PMID: 39578790 PMCID: PMC11583664 DOI: 10.1186/s12885-024-13133-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/30/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Research on the link between blood cell traits and cancer risk has gained significant attention. Traditional epidemiological and cell biology studies, have identified correlations between blood traits and cancer risks. These findings are important as they suggest potential risk factors and biological mechanisms. However, these studies often can't confirm causality, pointing to the need for further investigation to understand these relationships better. METHODS Mendelian randomization (MR), utilizing single-nucleotide polymorphisms as instrumental variables, was employed to investigate blood cell trait causal effects on cancer risk. Thirty-six blood cell traits were analyzed, and their impact on 28 major cancer outcomes was assessed using data from the FinnGen cohort, with eight major cancer outcomes and 22 cancer subsets. Furthermore, 1,008 MR analyses were conducted, incorporating sensitivity analyses (weighted median, MR-Egger, and MR-PRESSO) to address potential pleiotropy and heterogeneity. RESULTS The analysis (data from 173,480 individuals primarily of European descent) revealed significant results. An increase in eosinophil count was associated with a reduced risk of colorectal malignancies (OR = 0.7702 per 1 SD higher level, 95% CI = 0.6852 to 0.8658; P = 1.22E-05). Similarly, an increase in total eosinophil and basophil count was linked to a decreased risk of colorectal malignancies (OR = 0.7798 per 1 SD higher level, 95% CI = 0.6904 to 0.8808; P = 6.30E-05). Elevated hematocrit (HCT) levels were associated with a reduced risk of ovarian cancer (OR = 0.5857 per 1 SD higher level, 95% CI = 0.4443 to 0.7721; P = 1.47E-04). No significant heterogeneity or horizontal pleiotropy was observed. CONCLUSIONS Our study highlights the complex and context-dependent roles of blood cell traits in cancers.
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Affiliation(s)
- Jinghao Liang
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Xinyi Zhou
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Yijian Lin
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Hongming Yin
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Yuanqing Liu
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Zixian Xie
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Hongmiao Lin
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China
| | - Tongtong Wu
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Xinrong Zhang
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Zhaofeng Tan
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China
| | - Ziqiu Cheng
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Weiqiang Yin
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Zhihua Guo
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China.
| | - Wenzhe Chen
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China.
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Nov P, Li W, Wang D, Touch S, Kouy S, Ni P, Kou Q, Li Y, Zheng C, Prasai A, Fu W, Du K, Sou S, Li J. Basophils may as a risk factor for upper gastrointestinal cancer: a Mendelian randomization (MR) study. Ecancermedicalscience 2024; 18:1799. [PMID: 39816393 PMCID: PMC11735140 DOI: 10.3332/ecancer.2024.1799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Indexed: 01/18/2025] Open
Abstract
Objective Upper gastrointestinal (UGI) cancers, including esophageal (EC) and gastric (GC) cancers, pose a significant global health challenge. Previous studies have indicated a fundamental correlation between basophil count and the risk of UGI cancer. However, confirming a causal relationship demands further investigation. Mendelian randomization (MR) provides a critical method for evaluating the possible causal connections between peripheral circulating blood cells (PCBCs) and UGI cancer. Method Our study comprehensively employed a two-sample MR analysis. We used publicly available genetic data to survey the causal association between PCBC and UGI cancer. We used inverse variance weighting and weighted median for MR analyses and sensitivity analyses to assess heterogeneity and pleiotropy. Results In terms of the association between PCBCs and UGI cancer, we found that basophils count (EC: OR = 1.416, 95% CI = 1.125-1.783, p = 0.003; GC: OR = 1.623, 95% CI = 1.052-2.505, p = 0.029) were all strongly correlated with both EC and GC. Interestingly, Basophil count was a risk factor for both EC and GC. However, no significant correlations were seen between eosinophil, monocyte, lymphocyte or white blood cell count and UGI cancer. Conclusion The findings of this research corroborate the idea that basophils might serve as a fundamental risk factor for UGI cancer. Further exploration of the underlying mechanisms driving this relationship could provide crucial understanding helpful in creating prospective preventive and treatment methods for UGI cancer.
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Affiliation(s)
- Pengkhun Nov
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
- These authors contributed equally to this work
| | - Wandan Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
- These authors contributed equally to this work
| | - Duanyu Wang
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
- These authors contributed equally to this work
| | - Socheat Touch
- Department of Radiation Oncology, Luang Mè Hospital of University of Health Sciences, Street 109, Phnom Penh 120110, Cambodia
| | - Samnang Kouy
- Department of Radiation Oncology, Luang Mè Hospital of University of Health Sciences, Street 109, Phnom Penh 120110, Cambodia
| | - Peizan Ni
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Qianzi Kou
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Ying Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Chongyang Zheng
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Arzoo Prasai
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Wen Fu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Kunpeng Du
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
| | - Syphanna Sou
- Department of Radiation Oncology, Luang Mè Hospital of University of Health Sciences, Street 109, Phnom Penh 120110, Cambodia
| | - Jiqiang Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, No 253 Mid Gongye Ave, Haizhu District, Guangzhou 510282, Guangdong Province, China
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Pascal M, Bax HJ, Bergmann C, Bianchini R, Castells M, Chauhan J, De Las Vecillas L, Hartmann K, Álvarez EI, Jappe U, Jimenez-Rodriguez TW, Knol E, Levi-Schaffer F, Mayorga C, Poli A, Redegeld F, Santos AF, Jensen-Jarolim E, Karagiannis SN. Granulocytes and mast cells in AllergoOncology-Bridging allergy to cancer: An EAACI position paper. Allergy 2024; 79:2319-2345. [PMID: 39036854 DOI: 10.1111/all.16246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/23/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer.
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Affiliation(s)
- Mariona Pascal
- Immunology Department, CDB, Hospital Clínic de Barcelona; Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
- Department of Medicine, Universitat de Barcelona, Barcelona, Spain
- RETICS Asma, reacciones adversas y alérgicas (ARADYAL) and RICORS Red De Enfermedades Inflamatorias (REI), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Heather J Bax
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK
| | - Christoph Bergmann
- Department of Otorhinolaryngology, RKM740 Interdisciplinary Clinics, Düsseldorf, Germany
| | - Rodolfo Bianchini
- Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria
- The interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna, Vienna, Austria
| | - Mariana Castells
- Division of Allergy and Clinical Immunology, Drug Hypersensitivity and Desensitization Center, Mastocytosis Center, Brigham and Women's Hospital; Harvard Medical School, Boston, USA
| | - Jitesh Chauhan
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK
| | | | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland
- Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Elena Izquierdo Álvarez
- Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Institute of Applied Molecular Medicine Instituto de Medicina Molecular Aplicada Nemesio Díez (IMMA), Madrid, Spain
| | - Uta Jappe
- Division of Clinical and Molecular Allergology, Priority Research Area Chronic Lung Diseases, Research Center Borstel, Leibniz Lung Center, German Center for Lung Research (DZL), Airway Research Center North (ARCN), Borstel, Germany
- Interdisciplinary Allergy Outpatient Clinic, Department of Pneumology, University of Luebeck, Luebeck, Germany
| | | | - Edward Knol
- Departments Center of Translational Immunology and Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine. The Hebrew University of Jerusalem, Ein Kerem Campus, Jerusalem, Israel
| | - Cristobalina Mayorga
- RETICS Asma, reacciones adversas y alérgicas (ARADYAL) and RICORS Red De Enfermedades Inflamatorias (REI), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Allergy Unit and Research Laboratory, Hospital Regional Universitario de Málaga-HRUM, Instituto de investigación Biomédica de Málaga -IBIMA-Plataforma BIONAND, Málaga, Spain
| | - Aurélie Poli
- Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Frank Redegeld
- Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Alexandra F Santos
- Department of Women and Children's Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
- Children's Allergy Service, Evelina London Children's Hospital, Guy's and St Thomas' Hospital, London, UK
| | - Erika Jensen-Jarolim
- Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria
- The interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna, Vienna, Austria
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, UK
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Wei J, Mayberry CL, Lv X, Hu F, Khan T, Logan NA, Wilson JJ, Sears JD, Chaussabel D, Chang CH. IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity. Cancer Immunol Res 2024; 12:822-839. [PMID: 38739030 PMCID: PMC11219266 DOI: 10.1158/2326-6066.cir-23-0851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/14/2024] [Accepted: 05/07/2024] [Indexed: 05/14/2024]
Abstract
Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.
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Affiliation(s)
- Jian Wei
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
| | - Colleen L. Mayberry
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
| | - Xiaoting Lv
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
| | - Fangyan Hu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
| | - Taushif Khan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Natalie A. Logan
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
- Stanford University, Stanford, CA 94305, USA
| | - John J. Wilson
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
| | - John D. Sears
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Damien Chaussabel
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Chih-Hao Chang
- The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine, ME 04609, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA
- Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA
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Zhu JH, Xu BJ, Pang XY, Lian J, Gu K, Ji SJ, Lu HB. Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans. World J Oncol 2024; 15:482-491. [PMID: 38751703 PMCID: PMC11092417 DOI: 10.14740/wjon1860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/06/2024] [Indexed: 05/18/2024] Open
Abstract
Background Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans. Methods Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 participants) and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analyses were performed on East Asians and Europeans separately. Results Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69 - 0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77 - 0.97, P = 0.013). An inverse suggestive association was observed between levels of basophils and the risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72 - 0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57 - 0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70 - 0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67 - 0.94, P = 0.007). Conclusions Our MR analyses revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.
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Affiliation(s)
- Jia Hao Zhu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China
- These authors contributed equally to the study
| | - Ben Jie Xu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China
- These authors contributed equally to the study
| | - Xiang Yi Pang
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China
- These authors contributed equally to the study
| | - Jie Lian
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China
| | - Ke Gu
- Department of Radiotherapy and Oncology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, China
| | - Sheng Jun Ji
- Department of Radiotherapy and Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, China
| | - Hai Bo Lu
- Department of Outpatient Chemotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, China
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9
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Smorodin E, Chuzmarov V, Veidebaum T. The Potential of Integrative Cancer Treatment Using Melatonin and the Challenge of Heterogeneity in Population-Based Studies: A Case Report of Colon Cancer and a Literature Review. Curr Oncol 2024; 31:1994-2023. [PMID: 38668052 PMCID: PMC11049198 DOI: 10.3390/curroncol31040149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/19/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
Melatonin is a multifunctional hormone regulator that maintains homeostasis through circadian rhythms, and desynchronization of these rhythms can lead to gastrointestinal disorders and increase the risk of cancer. Preliminary clinical studies have shown that exogenous melatonin alleviates the harmful effects of anticancer therapy and improves quality of life, but the results are still inconclusive due to the heterogeneity of the studies. A personalized approach to testing clinical parameters and response to integrative treatment with nontoxic and bioavailable melatonin in patient-centered N-of-1 studies deserves greater attention. This clinical case of colon cancer analyzes and discusses the tumor pathology, the adverse effects of chemotherapy, and the dynamics of markers of inflammation (NLR, LMR, and PLR ratios), tumors (CEA, CA 19-9, and PSA), and hemostasis (D-dimer and activated partial thromboplastin time). The patient took melatonin during and after chemotherapy, nutrients (zinc, selenium, vitamin D, green tea, and taxifolin), and aspirin after chemotherapy. The patient's PSA levels decreased during CT combined with melatonin (19 mg/day), and melatonin normalized inflammatory markers and alleviated symptoms of polyneuropathy but did not help with thrombocytopenia. The results are analyzed and discussed in the context of the literature on oncostatic and systemic effects, alleviating therapy-mediated adverse effects, association with survival, and N-of-1 studies.
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Affiliation(s)
- Eugeniy Smorodin
- Department of Chronic Diseases, National Institute for Health Development, Paldiski mnt 80, 10617 Tallinn, Estonia;
| | - Valentin Chuzmarov
- 2nd Surgery Department, General Surgery and Oncology Surgery Centre, North Estonia Medical Centre, J. Sütiste Str. 19, 13419 Tallinn, Estonia
| | - Toomas Veidebaum
- Department of Chronic Diseases, National Institute for Health Development, Paldiski mnt 80, 10617 Tallinn, Estonia;
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10
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Constantinescu AE, Bull CJ, Jones N, Mitchell R, Burrows K, Dimou N, Bézieau S, Brenner H, Buchanan DD, D’Amato M, Jenkins MA, Moreno V, Pai RK, Um CY, White E, Murphy N, Gunter M, Timpson NJ, Huyghe JR, Vincent EE. Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study. Int J Cancer 2024; 154:94-103. [PMID: 37578112 PMCID: PMC10864681 DOI: 10.1002/ijc.34691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/06/2023] [Accepted: 07/17/2023] [Indexed: 08/15/2023]
Abstract
Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.
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Affiliation(s)
- Andrei-Emil Constantinescu
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
- School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Caroline J Bull
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
- School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Nicholas Jones
- Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom
| | - Ruth Mitchell
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia
- Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Mauro D’Amato
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Rish K Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Caroline Y Um
- Department of Population Science, American Cancer Society, Atlanta, Georgia, USA
| | - Emily White
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Marc Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
- School of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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11
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Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z, Wu K. Exploiting innate immunity for cancer immunotherapy. Mol Cancer 2023; 22:187. [PMID: 38008741 PMCID: PMC10680233 DOI: 10.1186/s12943-023-01885-w] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/28/2023] Open
Abstract
Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
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Affiliation(s)
- Ming Yi
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
| | - Bin Zhao
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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12
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Gao L, Yuan C, Fu J, Tian T, Huang H, Zhang L, Li D, Liu Y, Meng S, Liu Y, Zhang Y, Xu J, Jia C, Zhang D, Zheng T, Fu Q, Tan S, Lan L, Yang C, Zhao Y, Liu Y. Prognostic scoring system based on eosinophil- and basophil-related markers for predicting the prognosis of patients with stage II and stage III colorectal cancer: a retrospective cohort study. Front Oncol 2023; 13:1182944. [PMID: 37519795 PMCID: PMC10375403 DOI: 10.3389/fonc.2023.1182944] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/26/2023] [Indexed: 08/01/2023] Open
Abstract
Background Systemic inflammation is associated with the prognosis of colorectal cancer (CRC). The current study aimed to construct a comprehensively inflammatory prognostic scoring system named risk score (RS) based on eosinophil- and basophil-related markers and assess its prognostic value in patients with stage II and stage III CRC. Patients and methods A total of 3,986 patients were enrolled from January 2007 to December 2013. The last follow-up time was January 2019. They were randomly assigned to the training set and testing set in a 3:2 split ratio. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to select the optimal prognostic factors in the construction of RS. The Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC), and Cox analysis were used to evaluate the association between RS and overall survival (OS). Results In the training set, all inflammatory markers showed certain prognostic values. Based on LASSO-Cox analysis, nine markers were integrated to construct RS. The Kaplan-Meier curve showed that a higher RS (RS > 0) had a significantly worse prognosis (log-rank p< 0.0001). RS (>0) remained an independent prognostic factor for OS (hazard ratio (HR): 1.70, 95% confidence interval (CI), 1.43-2.03, p< 0.001). The prognostic value of RS was validated in the entire cohort. Time-dependent ROC analysis showed that RS had a stable prognostic effect throughout the follow-up times and could enhance the prognostic ability of the stage by combination. Nomogram was established based on RS and clinicopathological factors for predicting OS in the training set and validated in the testing set. The area under the curve (AUC) values of the 3-year OS in the training and testing sets were 0.748 and 0.720, respectively. The nomogram had a satisfactory predictive accuracy and had better clinical application value than the tumor stage alone. Conclusions RS might be an independent prognostic factor for OS in patients with stage II and III CRC, which is helpful for risk stratification of patients. Additionally, the nomogram might be used for personalized prediction and might contribute to formulating a better clinical treatment plan.
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Affiliation(s)
- Lijing Gao
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Chao Yuan
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Jinming Fu
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Tian Tian
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Hao Huang
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Lei Zhang
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Dapeng Li
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Yupeng Liu
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Shuhan Meng
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Ying Liu
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Yuanyuan Zhang
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Jing Xu
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Chenyang Jia
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Ding Zhang
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Ting Zheng
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingzhen Fu
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Shiheng Tan
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Li Lan
- Division of Chronic and Non-communicable Diseases, Harbin Center for Diseases Control and Prevention, Harbin, Heilongjiang, China
| | - Chao Yang
- Division of Chronic and Non-communicable Diseases, Harbin Center for Diseases Control and Prevention, Harbin, Heilongjiang, China
| | - Yashuang Zhao
- Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, Heilongjiang, China
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
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13
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Rimini M, Franco P, Bertolini F, Berardino DB, Giulia ZM, Stefano V, Andrikou K, Arcadipane F, Napolitano M, Buno LV, Alessandra GM, Olivero F, Ferreri F, Ricardi U, Cascinu S, Casadei-Gardini A. The Prognostic Role of Baseline Eosinophils in HPV-Related Cancers: a Multi-institutional Analysis of Anal SCC and OPC Patients Treated with Radical CT-RT. J Gastrointest Cancer 2023; 54:662-671. [PMID: 35915202 PMCID: PMC9342937 DOI: 10.1007/s12029-022-00850-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIM Anal squamous cell carcinoma (SCC) and oropharyngeal cancer (OPC) are rare tumors associated with HPV infection. Bioumoral predictors of response to chemoradiation (CT-RT) are lacking in these settings. With the aim to find new biomarkers, we investigated the role of eosinophils in both HPV-positive anal SCC and HPV-related oropharyngeal cancer (OPC). METHODS We retrieved clinical and laboratory data of patients with HPV-positive anal SCC treated with CT-RT in 5 institutions, and patients with locally advanced OPC SCC treated with CT-RT in 2 institutions. We examined the association between baseline eosinophil count (the best cutoff has been evaluated by ROC curve analysis: 100 × 10^9/L) and disease-free survival (DFS). Unadjusted and adjusted hazard ratios by baseline characteristics were calculated using the Cox proportional hazards model. RESULTS Three hundred four patients with HPV-positive anal SCCs and 168 patients with OPCs (122 HPV-positive, 46 HPV-negative diseases) were analyzed. In anal SCC, low eosinophil count (< 100 × 10^9/L) correlates to a better DFS (HR = 0.59; p = 0.0392); likewise, in HPV-positive OPC, low eosinophil count correlates to a better DFS (HR = 0.50; p = 0.0428). In HPV-negative OPC, low eosinophil count confers worse DFS compared to high eosinophil count (HR = 3.53; p = 0.0098). After adjustment for age and sex, eosinophils were confirmed to be independent prognostic factors for DFS (HR = 4.55; p = 0.0139). CONCLUSION Eosinophil count could be used as a prognostic factor in anal HPV-positive SCC. The worse prognosis showed in HPV-positive patients with high eosinophil count is likely to derive from an unfavorable interaction between the HPV-induced immunomodulation and eosinophils, which may hamper the curative effect of RT.
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Affiliation(s)
- Margherita Rimini
- Oncologic Department, IRCCS San Raffaele Scientific Institute Hospital, 20019, Milan, Italy
| | - Pierfrancesco Franco
- Department of Oncology - Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy.
| | - Federica Bertolini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - De Bari Berardino
- Radiation Oncology, Centre Hospitalier Universitaire de Besançon, 25000, Besançon cedex, France
- Radiation Oncology, Réseau Hospitalier Neuchâtelois, CH-2300, La Chaux-de-Fonds, Switzerland
| | - Zampino Maria Giulia
- Division of Radiation Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Vegge Stefano
- Radiation Oncology Department, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Kalliopi Andrikou
- Oncologic Department, Istituto Scientifico Romagnolo per lo Studio e la Cura Dei Tumori, IRCCS, Meldola (Forlì), Italy
| | - Francesca Arcadipane
- Department of Oncology - Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy
| | - Martina Napolitano
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Lavajo Vieira Buno
- Radiation Oncology, Centre Hospitalier Universitaire de Besançon, 25000, Besançon cedex, France
| | | | - Francesco Olivero
- Department of Oncology - Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy
| | - Filippo Ferreri
- Department of Oncology - Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy
| | - Umberto Ricardi
- Department of Oncology - Radiation Oncology, University of Turin School of Medicine, Via Genova 3, 10126, Turin, Italy
| | - Stefano Cascinu
- Oncologic Department, IRCCS San Raffaele Scientific Institute Hospital, 20019, Milan, Italy
| | - Andrea Casadei-Gardini
- Oncologic Department, IRCCS San Raffaele Scientific Institute Hospital, 20019, Milan, Italy
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14
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Luo L, Tan Y, Zhao S, Yang M, Che Y, Li K, Liu J, Luo H, Jiang W, Li Y, Wang W. The potential of high-order features of routine blood test in predicting the prognosis of non-small cell lung cancer. BMC Cancer 2023; 23:496. [PMID: 37264319 DOI: 10.1186/s12885-023-10990-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/21/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND Numerous studies have demonstrated that the high-order features (HOFs) of blood test data can be used to predict the prognosis of patients with different types of cancer. Although the majority of blood HOFs can be divided into inflammatory or nutritional markers, there are still numerous that have not been classified correctly, with the same feature being named differently. It is an urgent need to reclassify the blood HOFs and comprehensively assess their potential for cancer prognosis. METHODS Initially, a review of existing literature was conducted to identify the high-order features (HOFs) and classify them based on their calculation method. Subsequently, a cohort of patients diagnosed with non-small cell lung cancer (NSCLC) was established, and their clinical information prior to treatment was collected, including low-order features (LOFs) obtained from routine blood tests. The HOFs were then computed and their associations with clinical features were examined. Using the LOF and HOF data sets, a deep learning algorithm called DeepSurv was utilized to predict the prognostic risk values. The effectiveness of each data set's prediction was evaluated using the decision curve analysis (DCA). Finally, a prognostic model in the form of a nomogram was developed, and its accuracy was assessed using the calibration curve. RESULTS From 1210 documents, over 160 blood HOFs were obtained, arranged into 110, and divided into three distinct categories: 76 proportional features, 6 composition features, and 28 scoring features. Correlation analysis did not reveal a strong association between blood features and clinical features; however, the risk value predicted by the DeepSurv LOF- and HOF-models is significantly linked to the stage. Results from DCA showed that the HOF model was superior to the LOF model in terms of prediction, and that the risk value predicted by the blood data model could be employed as a complementary factor to enhance the prognosis of patients. A nomograph was created with a C-index value of 0.74, which is capable of providing a reasonably accurate prediction of 1-year and 3-year overall survival for patients. CONCLUSIONS This research initially explored the categorization and nomenclature of blood HOF, and proved its potential in lung cancer prognosis.
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Affiliation(s)
- Liping Luo
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yubo Tan
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Shixuan Zhao
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Man Yang
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yurou Che
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Kezhen Li
- School of Medicine, Southwest Medical University, Luzhou, China
| | - Jieke Liu
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Huaichao Luo
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Wenjun Jiang
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yongjie Li
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Weidong Wang
- Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
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15
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Willems M, Scherpereel A, Wasielewski E, Raskin J, Brossel H, Fontaine A, Grégoire M, Halkin L, Jamakhani M, Heinen V, Louis R, Duysinx B, Hamaidia M, Willems L. Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma. Front Immunol 2023; 14:1148798. [PMID: 37026006 PMCID: PMC10070849 DOI: 10.3389/fimmu.2023.1148798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/20/2023] [Indexed: 04/08/2023] Open
Abstract
Background Only a fraction of patients with malignant pleural mesothelioma (MPM) will respond to chemo- or immunotherapy. For the majority, the condition will irremediably relapse after 13 to 18 months. In this study, we hypothesized that patients' outcome could be correlated to their immune cell profile. Focus was given to peripheral blood eosinophils that, paradoxically, can both promote or inhibit tumor growth depending on the cancer type. Methods The characteristics of 242 patients with histologically proven MPM were retrospectively collected in three centers. Characteristics included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR). The mean absolute eosinophil counts (AEC) were determined by averaging AEC data sets of the last month preceding the administration of chemo- or immunotherapy. Results An optimal cutoff of 220 eosinophils/µL of blood segregated the cohort into two groups with significantly different median OS after chemotherapy (14 and 29 months above and below the threshold, p = 0.0001). The corresponding two-year OS rates were 28% and 55% in the AEC ≥ 220/µL and AEC < 220/µL groups, respectively. Based on shorter median PFS (8 vs 17 months, p < 0.0001) and reduced DCR (55.9% vs 35.2% at 6 months), the response to standard chemotherapy was significantly affected in the AEC ≥ 220/µL subset. Similar conclusions were also drawn from data sets of patients receiving immune checkpoint-based immunotherapy. Conclusion In conclusion, baseline AEC ≥ 220/µL preceding therapy is associated with worse outcome and quicker relapse in MPM.
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Affiliation(s)
- Mégane Willems
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Arnaud Scherpereel
- Department of Pneumology and Thoracic Oncology, (CHU Lille) and INSERM (ONCOTHAI), Lille, France
| | - Eric Wasielewski
- Department of Pneumology and Thoracic Oncology, (CHU Lille) and INSERM (ONCOTHAI), Lille, France
| | - Jo Raskin
- Department of Pulmonology and Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Hélène Brossel
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Alexis Fontaine
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Mélanie Grégoire
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Louise Halkin
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Majeed Jamakhani
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Vincent Heinen
- Department of Pneumology, University Hospital of Liege, Liege, Belgium
| | - Renaud Louis
- Department of Pneumology, University Hospital of Liege, Liege, Belgium
| | - Bernard Duysinx
- Department of Pneumology, University Hospital of Liege, Liege, Belgium
| | - Malik Hamaidia
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
| | - Luc Willems
- Laboratory of Molecular and Cellular Epigenetics (GIGA at University of Liege), Sart-Tilman, Molecular Biology, Teaching and Research Centre (TERRA), Gembloux, Belgium
- *Correspondence: Luc Willems,
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16
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Poto R, Gambardella AR, Marone G, Schroeder JT, Mattei F, Schiavoni G, Varricchi G. Basophils from allergy to cancer. Front Immunol 2022; 13:1056838. [PMID: 36578500 PMCID: PMC9791102 DOI: 10.3389/fimmu.2022.1056838] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022] Open
Abstract
Human basophils, first identified over 140 years ago, account for just 0.5-1% of circulating leukocytes. While this scarcity long hampered basophil studies, innovations during the past 30 years, beginning with their isolation and more recently in the development of mouse models, have markedly advanced our understanding of these cells. Although dissimilarities between human and mouse basophils persist, the overall findings highlight the growing importance of these cells in health and disease. Indeed, studies continue to support basophils as key participants in IgE-mediated reactions, where they infiltrate inflammatory lesions, release pro-inflammatory mediators (histamine, leukotriene C4: LTC4) and regulatory cytokines (IL-4, IL-13) central to the pathogenesis of allergic diseases. Studies now report basophils infiltrating various human cancers where they play diverse roles, either promoting or hampering tumorigenesis. Likewise, this activity bears remarkable similarity to the mounting evidence that basophils facilitate wound healing. In fact, both activities appear linked to the capacity of basophils to secrete IL-4/IL-13, with these cytokines polarizing macrophages toward the M2 phenotype. Basophils also secrete several angiogenic factors (vascular endothelial growth factor: VEGF-A, amphiregulin) consistent with these activities. In this review, we feature these newfound properties with the goal of unraveling the increasing importance of basophils in these diverse pathobiological processes.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy,Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy,World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy
| | - Adriana Rosa Gambardella
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy,Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy,World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy,Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), Naples, Italy
| | - John T. Schroeder
- Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD, United States
| | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy,*Correspondence: Gilda Varricchi, ; Giovanna Schiavoni,
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy,World Allergy Organization (WAO), Center of Excellence (CoE), Naples, Italy,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy,Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (CNR), Naples, Italy,*Correspondence: Gilda Varricchi, ; Giovanna Schiavoni,
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Wu Y, Li D, Wu M, Yang Y, Shen M, Chen K. Peripheral absolute eosinophil count identifies the risk of serious immune-related adverse events in non-small cell lung cancer. Front Oncol 2022; 12:1004663. [PMID: 36313675 PMCID: PMC9608122 DOI: 10.3389/fonc.2022.1004663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/29/2022] [Indexed: 12/02/2022] Open
Abstract
Background Immune-related adverse events (irAEs) have drawn a lot of attention lately as a result of the predominance of immunotherapy in advanced non-small cell lung cancer (NSCLC). However, the clinical evidence for irAEs in real life is limited. In this paper, the occurrence of irAEs in Chinese NSCLC patients was examined, and possible risk factors for the emergence of severe irAEs were discovered. Methods Our retrospective investigation assessed the occurrence of adverse events (AEs) and prognosis of 213 patients who received immunotherapy for NSCLC. Using univariate and multivariate logistic regression models, the association between clinicopathological traits and the incidence of severe irAEs was investigated. To assess the prognostic impact of irAEs, survival data was analyzed. Results Among the 213 NSCLC patients, 122 (57.3%) had irAEs of any grade, and 38 (17.8%) had high-grade (grade 3-5) AEs. Baseline peripheral absolute eosinophil count (AEC) (HR 6.58, 95% CI: 1.5-28.8, P=0.012) was found to be an independent predictor of high-grade irAEs by multivariate analysis. The survival analysis revealed that patients with severe irAEs had worse OS (15.7 vs. 20.8 months, 95% CI: 11.6-19.8 vs. 16.0-25.5, P=0.026). Conclusion According to our findings, the peripheral absolute eosinophil count (AEC) is a reliable indicator of severe irAEs in NSCLC. Serious irAEs that occur in patients often reflect poor prognoses. In the future, high-grade irAEs should receive more attention.
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Affiliation(s)
| | | | | | | | - Meng Shen
- *Correspondence: Kai Chen, ; Meng Shen,
| | - Kai Chen
- *Correspondence: Kai Chen, ; Meng Shen,
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18
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Ng L, Wan TMH, Iyer DN, Huang Z, Sin RWY, Man ATK, Li X, Foo DCC, Lo OSH, Law WL. High Levels of Tumor miR-187-3p—A Potential Tumor-Suppressor microRNA—Are Correlated with Poor Prognosis in Colorectal Cancer. Cells 2022; 11:cells11152421. [PMID: 35954265 PMCID: PMC9367907 DOI: 10.3390/cells11152421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/29/2022] [Accepted: 08/03/2022] [Indexed: 12/19/2022] Open
Abstract
Background: The microRNA miR-187-3p plays antitumor roles in a variety of cancers. We and others have previously identified miR-187-3p as a potential tumor suppressor in colorectal cancer (CRC), but there are also reports revealing that high miR-187-3p levels are associated with poor prognosis among CRC patients. This study further investigated the clinicopathological significance of miR-187-3p in CRC. Methods: MiR-187-3p levels in paired polyp/CRC/normal specimens or primary CRC/liver metastasis specimens were determined by qPCR, and correlated with the patient’s clinicopathological and postoperative survival data. The clinical findings were validated using our validation cohort and data obtained from the TCGA or GEO databases. The functional effects of miR-187-3p were investigated through its overexpression in CRC cell lines. Results: MiR-187-3p was significantly repressed in colorectal polyps and CRC when compared to adjacent normal tissue. Overexpression of miR-187-3p in CRC cell lines impaired colony formation, cell migration, and invasion, and induced chemosensitivity. Clinical analysis revealed that despite miR-187-3p being repressed in CRC, high tumor miR-187-3p levels were positively correlated with tumor stage and disease recurrence. Further analysis showed that miR-187-3p levels were lower in metastatic specimens when compared to paired primary CRC, suggesting that high tumor miR-187-3p levels resulted from the dissemination of metastatic tumor cells. Tumor miR-187-3p levels were positively correlated with peripheral inflammation-related blood markers. Finally, SPRY1 was identified as a novel target gene of miR-187-3p, and was involved in miR-187-3p-impaired CRC metastasis. Conclusions: This study demonstrated that in spite of its repression and role as a tumor suppressor in CRC, high levels of miR-187-3p in tumors were correlated with poor prognosis and higher levels of peripheral inflammation-related blood markers.
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Affiliation(s)
- Lui Ng
- Correspondence: (L.N.); (W.-L.L.)
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Weng M, Zhao W, Yue Y, Guo M, Nan K, Liao Q, Sun M, Zhou D, Miao C. High preoperative white blood cell count determines poor prognosis and is associated with an immunosuppressive microenvironment in colorectal cancer. Front Oncol 2022; 12:943423. [PMID: 35965545 PMCID: PMC9373020 DOI: 10.3389/fonc.2022.943423] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022] Open
Abstract
Background The correlation between high white blood cell (WBC) count and poor prognosis has been identified in various types of cancer; however, the clinical significance and immune context of WBC count in colorectal cancer remains unclear. Methods Between February 2009 and November 2014, 7,433 patients at the Shanghai Cancer Center who had undergone elective surgery for colorectal cancer were enrolled in this retrospective cohort study. Patients were divided into two groups: low and high preoperative WBC groups. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan-Meier method and Cox regression analysis were used to identify independent prognostic factors in colorectal cancer patients. Tumor-infiltrating immune cells in the high and low preoperative WBC groups were compared using immunohistochemical staining. Results Of the 7,433 patients who underwent colorectal cancer surgery and were available for analysis, 5,750 were included in the low preoperative WBC group, and 1,683 were included in the high preoperative WBC group. After propensity score matching, 1,553 patients were included in each group. Kaplan-Meier survival curves showed that a high preoperative WBC count was associated with a decreased overall survival (P = 0.002) and disease-free survival (P = 0.003), and that preoperative WBC count was an independent risk factor for overall survival (hazard ratio, 1.234; 95% confidence interval, 1.068-1.426; P = 0.004) and disease-free survival (hazard ratio, 1.210; 95% confidence interval, 1.047-1.397, P = 0.01). Compared to the low preoperative WBC group, the high preoperative WBC group exhibited higher expression of regulatory T cells (P = 0.0034), CD68+ macrophages (P = 0.0071), and CD66b+ neutrophils (P = 0.0041); increased expression of programmed cell death protein 1 (P = 0.005) and programmed cell death ligand 1 (P = 0.0019); and lower expression of CD8+ T cells (P = 0.0057) in colorectal cancer patients. Conclusions Our research indicates that a high preoperative WBC count is a prognostic indicator in colorectal cancer patients and is associated with an immunosuppressive tumor microenvironment, which could aid in future risk stratification.
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Affiliation(s)
- Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Wenling Zhao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ying Yue
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Miaomiao Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ke Nan
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Qingwu Liao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Minli Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Di Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
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20
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Hadadi A, Smith KE, Wan L, Brown JR, Russler G, Yantorni L, Caulfield S, Lafollette J, Moore M, Kucuk O, Carthon B, Nazha B, Liu Y, Bilen MA. Baseline basophil and basophil-to-lymphocyte status is associated with clinical outcomes in metastatic hormone sensitive prostate cancer. Urol Oncol 2022; 40:271.e9-271.e18. [PMID: 35466038 PMCID: PMC9117505 DOI: 10.1016/j.urolonc.2022.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/17/2022] [Accepted: 03/25/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Biomarkers have the potential to provide clinical guidance, but there is limited data for biomarkers in metastatic hormone sensitive prostate cancer (mHSPC). METHODS We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014-2020) in the United States of America (USA). We collected demographics, disease characteristics, and laboratory data, including complete blood counts (CBC) at the start of upfront therapy. We evaluated overall survival (OS) and progression-free survival (PFS) associated with baseline lab values. RESULTS 165 patients were included with a median follow-up time of 33.5 months (mo). 105 (63.6%) had Gleason scores of 8-10 and 108 (65.9%) were classified as high-volume disease. 92 patients received upfront docetaxel (55.8%) and 73 received upfront abiraterone (44.2%). Univariate analyses (UVA) and multivariable analyses (MVA) identified worse clinical outcomes (CO) associated with elevated basophils and basophil-to-lymphocyte ratio (BLR). Based on MVA, elevated basophils (defined as ≥0.1, optimal cut) were associated with a hazard ratio (HR) of 3.51 (95% CI 1.65-7.43, P 0.001) for OS and HR of 1.88 (95% CI 1.05-3.38, P 0.034) for PFS. Our MVA also found that BLR ≥0.0142 was associated with HR 2.11 (95% CI 1.09-4.10, P 0.028) for OS; however, PFS was not statistically significant. CONCLUSION We conclude that elevated baseline basophils and BLR are associated with worse clinical outcomes in mHSPC. Although results require further validation, BLR is a potential prognostic biomarker.
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Affiliation(s)
- Agreen Hadadi
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
| | - Katherine Er Smith
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
| | - Limeng Wan
- Departments of Biostatistics and Bioinformatics, Emory University, Atlanta, GA
| | - Jacqueline R Brown
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Greta Russler
- Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Lauren Yantorni
- Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Sarah Caulfield
- Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | | | - Melvin Moore
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Grady Cancer Center for Excellence, Grady Memorial Hospital, Atlanta, GA
| | - Omer Kucuk
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Grady Cancer Center for Excellence, Grady Memorial Hospital, Atlanta, GA
| | - Bradley Carthon
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Grady Cancer Center for Excellence, Grady Memorial Hospital, Atlanta, GA
| | - Bassel Nazha
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Grady Cancer Center for Excellence, Grady Memorial Hospital, Atlanta, GA
| | - Yuan Liu
- Departments of Biostatistics and Bioinformatics, Emory University, Atlanta, GA
| | - Mehmet A Bilen
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Grady Cancer Center for Excellence, Grady Memorial Hospital, Atlanta, GA.
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Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients. J Pers Med 2022; 12:jpm12050816. [PMID: 35629238 PMCID: PMC9146340 DOI: 10.3390/jpm12050816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.
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Detection of Specific Immune Cell Subpopulation Changes Associated with Systemic Immune Inflammation–Index Level in Germ Cell Tumors. Life (Basel) 2022; 12:life12050678. [PMID: 35629346 PMCID: PMC9147028 DOI: 10.3390/life12050678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 11/21/2022] Open
Abstract
The tumor microenvironment (TME) and the host inflammatory response are closely interconnected. The interplay between systemic inflammation and the local immune response may influence tumor development and progression in various types of cancer. The systemic immune–inflammation index (SII) represents a prognostic marker for germ cell tumors (GCTs). The aim of the present study was to detect specific immune cell subpopulation changes which were associated with the SII level in chemotherapy-naïve GCT patients. In total, 51 GCT patients, prior to cisplatin-based chemotherapy, were included in the present study. Immunophenotyping of peripheral blood leukocyte subpopulations was performed using flow cytometry. The SII level was correlated with the percentage of various leukocyte subpopulations. The obtained results demonstrated that SII levels above the cut-off value of SII ≥ 1003 were associated with higher neutrophil percentages. An inverse correlation was found between the SII and the peripheral lymphocyte percentage that logically reflects the calculations of the SII index. Furthermore, the presented data also showed that in the lymphocyte subpopulation, the association with the SII was driven by T-cell subpopulations. In innate immunity–cell subpopulations, we observed a correlation between SII level and neutrophils as well as associations with eosinophil, basophil, natural killer cell and dendritic cell percentages. We suppose that the described interactions represent a manifestation of cancer-induced immune suppression. The results of the present study contribute to the elucidation of the interrelationship between tumor cells and the innate/adaptive immune system of the host.
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Kalavska K, Sestakova Z, Mlcakova A, Gronesova P, Miskovska V, Rejlekova K, Svetlovska D, Sycova-Mila Z, Obertova J, Palacka P, Mardiak J, Chovanec M, Chovanec M, Mego M. Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients. Front Oncol 2022; 12:858797. [PMID: 35359385 PMCID: PMC8963339 DOI: 10.3389/fonc.2022.858797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innate/adaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innate/adaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innate/adaptive immune response in GCT patients.
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Affiliation(s)
- Katarina Kalavska
- Translational Research Unit, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Zuzana Sestakova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Department of Laboratory Medicine, National Institute of Children's Diseases, Bratislava, Slovakia
| | - Andrea Mlcakova
- Department of Hematology, National Cancer Institute, Bratislava, Slovakia
| | - Paulina Gronesova
- Department of Tumor Immunology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Viera Miskovska
- 1Department of Oncology, Faculty of Medicine, St. Elisabeth Cancer Institute, Comenius University, Bratislava, Slovakia
| | - Katarina Rejlekova
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Daniela Svetlovska
- Translational Research Unit, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
| | | | - Jana Obertova
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Patrik Palacka
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Jozef Mardiak
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Miroslav Chovanec
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Michal Chovanec
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
| | - Michal Mego
- Translational Research Unit, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- 2Department of Oncology, Faculty of Medicine, National Cancer Institute, Comenius University, Bratislava, Slovakia
- Department of Oncology, National Cancer Institute, Bratislava, Slovakia
- *Correspondence: Michal Mego,
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Stephen B, Hajjar J. Immune System in Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:1-43. [PMID: 34972961 DOI: 10.1007/978-3-030-79308-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells is found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the crosstalk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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Affiliation(s)
- Bettzy Stephen
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Joud Hajjar
- Assistant Professor, Service Chief of Adult Allergy & Immunology, Division of Immunology, Allergy & Retrovirology, Baylor College of Medicine and Texas Children' Hospital, Houston, TX, USA
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Comprehensive Statistical Exploration of Prognostic (Bio-)Markers for Responses to Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer. Cancers (Basel) 2021; 14:cancers14010075. [PMID: 35008239 PMCID: PMC8750624 DOI: 10.3390/cancers14010075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Metastatic non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) may suffer from heavy side effects, and not all patients benefit from the treatment. Therefore, it is crucial to gain knowledge about possible (bio-)markers for response to ICIs. We used retrospective data acquired from NSCLC patients treated with ICIs in first- or further-line therapy settings, including 16 possible markers. We conducted a comprehensive statistical analysis study to find markers for response to treatment, assessed the robustness of our results, and discussed often encountered statistical pitfalls. Our study yielded hypotheses for various predictive and prognostic (bio-)markers for response to ICIs in NSCLC patients. In particular, we found that high basophil counts may be predictive for treatment response in patients in further-line therapy settings. Abstract Metastatic non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) may suffer from heavy side effects and not all patients benefit from the treatment. We conducted a comprehensive statistical analysis to identify promising (bio-)markers for treatment response. We analyzed retrospective data from NSCLC patients treated with ICIs in first- or further-line therapy settings at the University Hospital Zurich. We investigated 16 possible prognostic markers with respect to overall survival, tumor size reduction, and the development of an immune-related adverse event (irAE) and assessed the robustness of our results. For the further-line patient group, the most significant result was that increased basophil counts were associated with increased odds of tumor size reduction within three months and with the development of an irAE. For the first-line patient group, the most significant results were that increased lymphocyte counts, the histology of adenocarcinoma, and the intake of non-steroidal anti-rheumatic drugs (NSAR) were associated with decreased hazards of dying. Our study yielded new hypotheses for predictive (bio-)markers for response to ICIs in NSCLC patients. The possibly beneficial role of high basophil counts is a particularly interesting finding. Our results should be tested on independent data in a prospective fashion.
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White Blood Cells in Patients Treated with Programmed Cell Death-1 Inhibitors for Non-small Cell Lung Cancer. Lung 2021; 199:549-557. [PMID: 34518898 PMCID: PMC8510914 DOI: 10.1007/s00408-021-00474-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/02/2021] [Indexed: 12/26/2022]
Abstract
Purpose To investigate whether eosinophils and other white blood cell subtypes could be used as response and prognostic markers to anti-Programmed cell Death-1 or anti-PD-Ligand-1 treatments in non-small cell lung cancer patients. Methods We retrospectively analyzed data from the NSCLC patients consecutively treated at our hospital with a PD-1/PD-L1 inhibitor in monotherapy for advanced disease. A total of 191 patients were evaluated at three time-points to investigate any relation between tumor response and WBC counts. Results Baseline WBC and subtypes did not differ according to the type of response seen under treatment. A higher relative eosinophil count (REC) correlated with more objective responses (p = 0.019 at t1 and p = 0.014 at t2; OR for progression = 0.54 and 0.53, respectively) independently of the smoking status, PD-L1 status, and immune-related toxicity (IRT). Higher REC was also associated with a longer duration of treatment (p = 0.0096). Baseline absolute neutrophil count was prognostic (p = 0.049). At t1 relative lymphocytes, absolute and relative neutrophils, and neutrophil-to-lymphocyte ratio were prognostic (p = 0.044, p = 0.014, p = 0.0033, and p = 0.029, respectively). Conclusion Our results show that in NSCLC patients anti-PD-1/PD-L1 therapy induces an early increase only in blood eosinophils, more prominent in responding patients and independent of the smoking status, PD-L1 status, and IRT. Eosinophils are also associated with a longer duration of treatment. Furthermore, our data support a prognostic role of neutrophils, lymphocytes, and their ratio for NSCLC patients with advanced disease treated with PD(L)-1 blockade.
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Naszai M, Kurjan A, Maughan TS. The prognostic utility of pre-treatment neutrophil-to-lymphocyte-ratio (NLR) in colorectal cancer: A systematic review and meta-analysis. Cancer Med 2021; 10:5983-5997. [PMID: 34308567 PMCID: PMC8419761 DOI: 10.1002/cam4.4143] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/03/2021] [Accepted: 07/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Inflammation is a hallmark of cancer, and systemic markers of inflammation are increasingly recognised as negative prognostic factors for clinical outcome. Neutrophil‐to‐lymphocyte ratio (NLR) is readily available from routine blood testing of patients diagnosed with cancer. Methods Peer‐reviewed publications from PubMed/MEDLINE, Web of Science and EMBASE were identified according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines. Hazard ratios (HR) for overall survival (OS) and surrogate endpoints (SE; comprising disease‐, recurrence‐ and progression‐free survival) were pooled using a random effects model. Additional analysis was carried out to further investigate NLR as an independent prognostic factor and account for heterogeneity. Results Seventy‐one eligible papers comprising 32,788 patients were identified. High NLR was associated with poor clinical outcomes. Significant publication bias was observed, and larger studies also adjusted for more covariates. Correcting for publication bias in multivariate studies brought our best estimate for true effect size to HR = 1.57 (95% CI 1.39–1.78; p < 0.0001) for OS and to HR = 1.38 (95% CI 1.16–1.64; p = 0.0003) for SE. Conclusions NLR is confirmed as an easily available prognostic biomarker in colorectal cancer, despite the limitations of some studies previously reporting this finding. As such, it should be routinely collected in prospective clinical trials. While more standardised and rigorous large‐scale studies are needed before high NLR can be fully assessed as an independent predictor of CRC progression and outcome, the data suggest that it may be used to highlight individuals with tumour‐promoting inflammatory context.
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Affiliation(s)
- Mate Naszai
- Medical Sciences Division, University of Oxford, Oxford, UK
| | - Alina Kurjan
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK
| | - Timothy S Maughan
- MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
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The Janus Face of IL-33 Signaling in Tumor Development and Immune Escape. Cancers (Basel) 2021; 13:cancers13133281. [PMID: 34209038 PMCID: PMC8268428 DOI: 10.3390/cancers13133281] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/25/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Interleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target. Abstract Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8+ T cells, regulatory T cells (Treg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy.
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Valero C, Zanoni DK, Pillai A, Ganly I, Morris LGT, Shah JP, Wong RJ, Patel SG. Host Factors Independently Associated With Prognosis in Patients With Oral Cavity Cancer. JAMA Otolaryngol Head Neck Surg 2021; 146:699-707. [PMID: 32525545 DOI: 10.1001/jamaoto.2020.1019] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Importance The association and interaction of host characteristics with prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are poorly understood. There is increasing evidence that host characteristics are associated with treatment outcomes of many cancers. Objectives To examine the host factors associated with prognosis in patients with OSCC and their interactions to create a numerical index that quantifies the prognostic capacity of these host characteristics. Design, Setting, and Participants This retrospective cohort study included patients with OSCC treated surgically at a tertiary care center from January 1, 1998, to December 31, 2015. From a departmental OSCC database of 1377 previously untreated patients, 68 patients with missing data on any host variable of interest within a month before the start of treatment were excluded, leaving 1309 patients. Data analysis was performed from October 21, 2019, to December 10, 2019. Exposure Primary surgery for OSCC. Main Outcomes and Measures Overall survival (OS) was the primary end point, and disease-specific survival (DSS) was the secondary end point. Optimal cutoffs for each variable were identified using recursive-partitioning analysis with the classification and regression tree method using OS as the dependent variable. Body mass index (BMI) and pretreatment peripheral blood leukocyte count, platelet count, hemoglobin level, and albumin level were analyzed. A host index (H-index) was developed using independent factors associated with OS. Results A total of 1309 patients (731 [55.8%] male; mean [SD] age, 62 [14.3] years) participated in the study. When including all the host-related factors in a multivariable analysis, all except BMI (hazard ratio [HR], 1.14; 95% CI, 0.80-1.63) were independently associated with outcomes. For example, compared with a hemoglobin level of 14.1 g/dL or greater, the HR for a level of 12.9 to 14.0 g/dL was 1.42 (95% CI, 1.13-1.77) and for a level of 12.8 g/dL or less was 1.51 (95% CI, 1.18-1.94), and compared with an albumin level of 4.3 g/dL or greater, the HR for a level of 3.7 to 4.2 g/dL was 1.18 (95% CI, 0.95-1.45) and for a level of 3.6 g/dL or less was 3.64 (95% CI, 2.37-5.58). An H-index of 1.4 or less was associated with a 74% 5-year OS, an H-index of 1.5 to 3.5 with a 65% 5-year OS, and an H-index of 3.6 or higher with a 38% 5-year OS; for DSS, the 5-year survival was 84%, 80%, and 64%, respectively. Compared with patients with an H-index score of 1.4 or less, patients with H-index scores of 1.5 to 3.5 (hazard ratio, 1.474; 95% CI, 1.208-1.798) and 3.6 or higher (hazard ratio, 3.221; 95% CI, 2.557-4.058) had a higher risk of death. Conclusions and Relevance The findings suggest that pretreatment values of neutrophils, monocytes, lymphocytes, hemoglobin, and albumin are independently associated with prognosis in patients with OSCC. The interactions between these host factors were incorporated into a novel H-index that quantified the prognostic capacity of host characteristics associated with OSCC.
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Affiliation(s)
- Cristina Valero
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Daniella K Zanoni
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anjali Pillai
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ian Ganly
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Luc G T Morris
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jatin P Shah
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Oncology, Radiotherapy and Plastic Surgery, Sechenov University, Moscow, Russia
| | - Richard J Wong
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Snehal G Patel
- Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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Siemińska I, Poljańska E, Baran J. Granulocytes and Cells of Granulocyte Origin-The Relevant Players in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22073801. [PMID: 33917620 PMCID: PMC8038777 DOI: 10.3390/ijms22073801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact in CRC development. The risk of CRC is attributed, among others to dietary habits, alcohol consumption, whereas physical activity, food containing dietary fiber, dairy products, and calcium supplements have a protective effect. Despite progress in the available therapies, surgery remains a basic treatment option for CRC. Implementation of additional methods of treatment such as chemo- and/or targeted immunotherapy, improved survival rates, however, the results are still far from satisfactory. One of the reasons may be the lack of deeper understanding of the interactions between the tumor and different types of cells, including tumor infiltrating granulocytes. While the role of neutrophils is quite well explored in many cancers, role of eosinophils and basophils is often underestimated. As part of this review, we focused on the function of different granulocyte subsets in CRC, emphasizing the beneficial role of eosinophils and basophils, as well as dichotomic mode of neutrophils action. In addition, we addressed the current knowledge on cells of granulocyte origin, specifically granulocytic myeloid derived suppressor cells (Gr-MDSCs) and their role in development and progression of CRC.
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Affiliation(s)
- Izabela Siemińska
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland;
| | - Ewa Poljańska
- Laboratory Medicine, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland;
| | - Jarek Baran
- Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Krakow, Poland;
- Correspondence:
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Zheng L, Yu M, Zhang S. Prognostic value of pretreatment circulating basophils in patients with glioblastoma. Neurosurg Rev 2021; 44:3471-3478. [PMID: 33765226 DOI: 10.1007/s10143-021-01524-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/07/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
Accumulating evidence demonstrated that atopic diseases were inversely related to glioma susceptibility and associated with improved prognosis of patients with glioma. This study aimed to elucidate the impacts of basophils, one of the important effector cells in the pathobiology of atopic disease, on prognosis of patients with glioblastoma (GBM). A total of 268 patients were newly diagnosed with GBM and treated with operation at our institution from January 2010 to December 2017. The association between pre-operation circulating eosinophil, basophil, neutrophil, lymphocyte, monocyte count and GBM progression free survival (PFS) was investigated. Moreover, based on the results of multivariate analysis, a prognostic nomogram was established and evaluated. Kaplan-Meier method showed that basophils ≥0.015 × 109/L (p = 0.015) and lymphocytes ≥1.555 × 109/L (p = 0.005) were correlated with better PFS. Cox regression model showed that basophils ≥0.015 × 109/L were an independent prognostic factor for PFS. Prognostic nomogram was established and the concordance index (C-index) for PFS prediction was 0.629. The calibration plots for the probability of 0.5-, 1- and 3-year PFS showed optimal consistency between the prediction by nomogram and actual observation. Increased pre-operation circulating basophils portend better PFS, which might be a useful and novel marker for the prognosis of GBM patients.
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Affiliation(s)
- Lingnan Zheng
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Gaopeng Street, Keyuan Road 4, Chengdu, 610041, Sichuan, China
| | - Min Yu
- Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuang Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Gaopeng Street, Keyuan Road 4, Chengdu, 610041, Sichuan, China.
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Rimini M, Franco P, De Bari B, Zampino MG, Vagge S, Frassinetti GL, Arcadipane F, Bacigalupo A, Valgiusti M, Aloi D, Gervaso L, Corvò R, Bartolini G, Gerardi MA, Cascinu S, Casadei-Gardini A. The Prognostic Value of the New Combined Hemo-Eosinophil Inflammation Index (HEI Index): A Multicenter Analysis of Anal Cancer Patients Treated with Concurrent Chemo-Radiation. Cancers (Basel) 2021; 13:671. [PMID: 33562397 PMCID: PMC7914854 DOI: 10.3390/cancers13040671] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 12/27/2022] Open
Abstract
Anal squamous cell carcinoma (SCC) is a rare tumor, and bio-humoral predictors of response to chemo-radiation (CT-RT) are lacking. We developed a prognostic score system based on laboratory inflammation parameters. We investigated the correlation between baseline clinical and laboratory variables and disease-free (DFS) and overall (OS) survival in anal SCC patients treated with CT-RT in five institutions. The bio-humoral parameters of significance were included in a new scoring system, which was tested with other significant variables in a Cox's proportional hazard model. A total of 308 patients was included. We devised a prognostic model by combining baseline hemoglobin level, SII, and eosinophil count: the Hemo-Eosinophils Inflammation (HEI) Index. We stratified patients according to the HEI index into low- and high-risk groups. Median DFS for low-risk patients was not reached, and it was found to be 79.5 months for high-risk cases (Hazard Ratio 3.22; 95% CI: 2.04-5.10; p < 0.0001). Following adjustment for clinical covariates found significant at univariate analysis, multivariate analysis confirmed the HEI index as an independent prognostic factor for DFS and OS. The HEI index was shown to be a prognostic parameter for DFS and OS in anal cancer patients treated with CT-RT. An external validation of the HEI index is mandatory for its use in clinical practice.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, 41000 Modena, Italy;
| | - Pierfrancesco Franco
- Department of Oncology, Radiation Oncology, University of Turin, 10126 Turin, Italy;
| | - Berardino De Bari
- Department of Radiation Oncology, University Hospital of Besançon, 25000 Besançon, France; (B.D.B.); (D.A.)
- Department of Radiation Oncology, Réseau Hospitalier Neuchâtelois, 2300 La Chaux-de-Fonds, Switzerland
| | - Maria Giulia Zampino
- Division of Gastrointestinal Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, 20019 Milan, Italy; (M.G.Z.); (L.G.)
| | - Stefano Vagge
- Department of Radiation Oncology, IRCCS Ospedale Policlinico San Martino, 16121 Genova, Italy; (S.V.); (A.B.)
| | - Giovanni Luca Frassinetti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori ‘Dino Amadori’–IRST, 47014 Meldola, Italy; (G.L.F.); (M.V.); (G.B.)
| | - Francesca Arcadipane
- Department of Oncology, Radiation Oncology, University of Turin, 10126 Turin, Italy;
| | - Almalina Bacigalupo
- Department of Radiation Oncology, IRCCS Ospedale Policlinico San Martino, 16121 Genova, Italy; (S.V.); (A.B.)
| | - Martina Valgiusti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori ‘Dino Amadori’–IRST, 47014 Meldola, Italy; (G.L.F.); (M.V.); (G.B.)
| | - Deborah Aloi
- Department of Radiation Oncology, University Hospital of Besançon, 25000 Besançon, France; (B.D.B.); (D.A.)
| | - Lorenzo Gervaso
- Division of Gastrointestinal Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, 20019 Milan, Italy; (M.G.Z.); (L.G.)
| | - Renzo Corvò
- Department of Radiation Oncology, IRCCS Ospedale Policlinico San Martino and Health Science Department (DISSAL), University of Genova, 16121 Genova, Italy;
| | - Giulia Bartolini
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori ‘Dino Amadori’–IRST, 47014 Meldola, Italy; (G.L.F.); (M.V.); (G.B.)
| | | | - Stefano Cascinu
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, 20019 Milan, Italy; (S.C.); (A.C.-G.)
| | - Andrea Casadei-Gardini
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, 20019 Milan, Italy; (S.C.); (A.C.-G.)
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Ohkuma R, Kubota Y, Horiike A, Ishiguro T, Hirasawa Y, Ariizumi H, Watanabe M, Onoue R, Ando K, Tsurutani J, Yoshimura K, Aoki T, Murakami M, Kobayashi S, Tsunoda T, Wada S. The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer. Pancreas 2021; 50:167-175. [PMID: 33565793 DOI: 10.1097/mpa.0000000000001731] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection. METHODS This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves. RESULTS The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes. CONCLUSIONS Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.
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Affiliation(s)
| | - Yutaro Kubota
- Division of Medical Oncology, Department of Medicine, School of Medicine
| | - Atsushi Horiike
- Division of Medical Oncology, Department of Medicine, School of Medicine
| | - Tomoyuki Ishiguro
- Division of Medical Oncology, Department of Medicine, School of Medicine
| | - Yuya Hirasawa
- Division of Medical Oncology, Department of Medicine, School of Medicine
| | - Hirotsugu Ariizumi
- Division of Medical Oncology, Department of Medicine, School of Medicine
| | - Makoto Watanabe
- From the Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics
| | - Rie Onoue
- From the Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics
| | - Kiyohiro Ando
- From the Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics
| | | | | | - Takeshi Aoki
- Division of General and Gastroenterological Surgery, Department of Surgery, School of Medicine, Showa University, Tokyo, Japan
| | - Masahiko Murakami
- Division of General and Gastroenterological Surgery, Department of Surgery, School of Medicine, Showa University, Tokyo, Japan
| | | | - Takuya Tsunoda
- Division of Medical Oncology, Department of Medicine, School of Medicine
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Domagala M, Laplagne C, Leveque E, Laurent C, Fournié JJ, Espinosa E, Poupot M. Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells. Cancers (Basel) 2021; 13:E165. [PMID: 33418996 PMCID: PMC7825276 DOI: 10.3390/cancers13020165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 12/11/2022] Open
Abstract
Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance.
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Affiliation(s)
- Marcin Domagala
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Chloé Laplagne
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Edouard Leveque
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Camille Laurent
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
- IUCT-O, 31000 Toulouse, France
| | - Jean-Jacques Fournié
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Eric Espinosa
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
| | - Mary Poupot
- Centre de Recherches en Cancérologie de Toulouse, Inserm UMR1037, 31037 Toulouse, France; (M.D.); (C.L.); (E.L.); (C.L.); (J.-J.F.); (E.E.)
- Université Toulouse III Paul-Sabatier, 31400 Toulouse, France
- ERL 5294 CNRS, 31037 Toulouse, France
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Boyle ST, Johan MZ, Samuel MS. Tumour-directed microenvironment remodelling at a glance. J Cell Sci 2020; 133:133/24/jcs247783. [PMID: 33443095 DOI: 10.1242/jcs.247783] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The tissue microenvironment supports normal tissue function and regulates the behaviour of parenchymal cells. Tumour cell behaviour, on the other hand, diverges significantly from that of their normal counterparts, rendering the microenvironment hostile to tumour cells. To overcome this problem, tumours can co-opt and remodel the microenvironment to facilitate their growth and spread. This involves modifying both the biochemistry and the biophysics of the normal microenvironment to produce a tumour microenvironment. In this Cell Science at a Glance article and accompanying poster, we outline the key processes by which epithelial tumours influence the establishment of the tumour microenvironment. As the microenvironment is populated by genetically normal cells, we discuss how controlling the microenvironment is both a significant challenge and a key vulnerability for tumours. Finally, we review how new insights into tumour-microenvironment interactions has led to the current consensus on how these processes may be targeted as novel anti-cancer therapies.
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Affiliation(s)
- Sarah T Boyle
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - M Zahied Johan
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia
| | - Michael S Samuel
- Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia .,Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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Prognostic Inflammatory Index Based on Preoperative Peripheral Blood for Predicting the Prognosis of Colorectal Cancer Patients. Cancers (Basel) 2020; 13:cancers13010003. [PMID: 33374924 PMCID: PMC7792597 DOI: 10.3390/cancers13010003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/08/2020] [Accepted: 12/19/2020] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Inflammation plays a critical role in the progression of colorectal cancer (CRC). Peripheral blood cell counts could reflect the extent of systemic inflammation and are readily available in clinical practice. The aim of our study was to construct a novel prognostic inflammatory index (PII) by integrating the blood cell counts associated with prognosis and to evaluate and validate the prognostic value of PII in two independent CRC cohorts. Multivariate Cox analyses in the training cohort of 4154 CRC patients indicated that high OS-PII (>4.27) and high DFS-PII (>4.47) were significantly associated with worse OS (HR: 1.330, p < 0.001) and worse DFS (HR: 1.366, p < 0.001), which has been validated in the external validation cohort of 5161 patients. Both OS-PII and DFS-PII have a stable prognostic performance at various follow-up times, and the nomograms based on OS-PII and DFS-PII achieved good accuracy in personalized survival prediction of patients with CRC. Abstract Host inflammation is a critical component of tumor progression and its status can be indicated by peripheral blood cell counts. We aimed to construct a comprehensively prognostic inflammatory index (PII) based on preoperative peripheral blood cell counts and further evaluate its prognostic value for patients with colorectal cancer (CRC). A total of 9315 patients with stage II and III CRC from training and external validation cohorts were included. The PII was constructed by integrating all the peripheral blood cell counts associated with prognosis in the training cohort. Cox analyses were performed to evaluate the association between PII and overall survival (OS) and disease-free survival (DFS). In the training cohort, multivariate Cox analyses indicated that high OS-PII (>4.27) was significantly associated with worse OS (HR: 1.330, 95% CI: 1.189–1.489, p < 0.001); and high DFS-PII (>4.47) was significantly associated with worse DFS (HR: 1.366, 95% CI: 1.206–1.548, p < 0.001). The prognostic values of both OS-PII and DFS-PII were validated in the external validation cohort. The nomograms achieved good accuracy in predicting both OS and DFS. Time-dependent ROC analyses showed that both OS-PII and DFS-PII have a stable prognostic performance at various follow-up times. The prognostic value of tumor-node-metastasis staging could be enhanced by combining it with either OS-PII or DFS-PII. We demonstrated that PIIs are independent prognostic predictors for CRC patients, and the nomograms based on PIIs can be recommended for personalized survival prediction of patients with CRC.
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Gamez-Belmonte R, Erkert L, Wirtz S, Becker C. The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses. Int J Mol Sci 2020; 21:ijms21249772. [PMID: 33371444 PMCID: PMC7767427 DOI: 10.3390/ijms21249772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.
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Orsi G, Tovoli F, Dadduzio V, Vivaldi C, Brunetti O, Ielasi L, Conti F, Rovesti G, Gramantieri L, Rizzato MD, Pecora I, Argentiero A, Teglia F, Lonardi S, Salani F, Granito A, Zagonel V, Marisi G, Cabibbo G, Foschi FG, Benevento F, Cucchetti A, Piscaglia F, Cascinu S, Scartozzi M, Casadei-Gardini A. Prognostic Role of Blood Eosinophil Count in Patients with Sorafenib-Treated Hepatocellular Carcinoma. Target Oncol 2020; 15:773-785. [PMID: 33044683 DOI: 10.1007/s11523-020-00757-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. OBJECTIVE The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. PATIENTS AND METHODS A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6-216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24-16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83-5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. CONCLUSIONS Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.
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Affiliation(s)
- Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Via del Pozzo 71, Modena, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Vincenzo Dadduzio
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Caterina Vivaldi
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
- Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Via Savi 6, Pisa, 56126, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Luca Ielasi
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Fabio Conti
- Department of Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Via del Pozzo 71, Modena, Italy
| | - Laura Gramantieri
- Center for Applied Biomedical Research (CRBa), St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Mario Domenico Rizzato
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Irene Pecora
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
| | | | - Federica Teglia
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Sara Lonardi
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Francesca Salani
- Division of Medical Oncology 2, Pisa University Hospital, Pisa, Italy
| | - Alessandro Granito
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifco Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | | | - Francesca Benevento
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Division of Internal Medicine, Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy
| | - Stefano Cascinu
- Vita-Salute San Rafaele University, Milan, Italy
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy
| | - Mario Scartozzi
- Department of Medical Oncology, University Hospital of Cagliari, Cagliari, Italy
| | - Andrea Casadei-Gardini
- Vita-Salute San Rafaele University, Milan, Italy.
- Department of Medical Oncology, San Rafaele Scientifc Institute IRCCS, Milan, Italy.
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Liu X, Wang J. The nucleosome remodeling and deacetylase complex has prognostic significance and associates with immune microenvironment in skin cutaneous melanoma. Int Immunopharmacol 2020; 88:106887. [PMID: 32799111 DOI: 10.1016/j.intimp.2020.106887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/04/2020] [Accepted: 08/07/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE The Nucleosome Remodeling and Deacetylase (NuRD) complex is an important marker in multiple biological processes whose clinical significance has rarely previously been reported in cancers. In this study, we proposed to estimate the potential of NuRD complex as prognostic signature in skin cutaneous melanoma (SKCM) patients. METHODS SKCM samples were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Sample clustering was performed based on the mRNA levels of core subunits of NuRD complex. Survival analysis was carried out by using Kaplan-Meier method. SKCM samples were grouped into prognostically good and poor groups according to their overall survival (OS). Logistic regression analysis was adopted to construct a model based on the optimal subunits of NuRD complex to estimate prognosis of SKCM samples. RESULTS Samples from TCGA were grouped into four clusters which were then divided into good and poor prognostic groups. Significant differences existed in immune microenvironment and mutational rates of frequently mutated genes between good and poor prognostic groups. Besides, several immune-related pathways were significantly activated in good prognostic group. A logistic regression model was constructed by using patients' prognostic group and mRNA expressions of NuRD complex from TCGA as categorical responsive values and continuous predictive variables, respectively, which could independently distinguish prognostically different SKCM patients from another three independent GEO datasets. CONCLUSION In conclusion, we first reported the potential prognostic value and roles in immune microenvironment of NuRD complex in SKCM, which should be helpful for experimental and clinical research in SKCM.
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Affiliation(s)
- Xinhua Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
| | - Ju Wang
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, PR China.
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Ren Z, Liu J, Yao L, Li J, Qi Z, Li B. Glutamate receptor ionotropic, kainate 1 serves as a novel tumor suppressor of colorectal carcinoma and predicts clinical prognosis. Exp Ther Med 2020; 20:167. [PMID: 33093905 DOI: 10.3892/etm.2020.9296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 07/10/2020] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most malignant cancers worldwide. However, the mechanisms of initiation and development of CRC are still largely unclear. The present study aimed to investigate the biological function and prognosis of glutamate receptor ionotropic, kainate 1 (GRIK1) in CRC. GRIK1 expression levels were analyzed in tissue microarrays containing 80 primary CRC samples using immunohistochemistry (IHC). The association between GRIK1 expression levels, clinicopathological factors and the prognosis was also investigated using Spearman's correlation analysis and Kaplan-Meier analysis, respectively. After genetic knockdown or overexpression of GRIK1, invasion/migration assays, proliferation assay, soft agar/colony formation assays, western blotting, reverse transcription-quantitative PCR and tumor xenograft models were used to investigate the function of GRIK1 both in vitro in two CRC cell lines, HCT116 and SW620, and in vivo. The results revealed that the expression levels of GRIK1 were significantly downregulated in CRC samples. Furthermore, IHC analysis indicated that the downregulated expression levels of GRIK1 were significantly associated with lymph node status and tumor size. In addition, patients with CRC with low GRIK1 expression levels demonstrated a consistently poor overall survival. The overexpression of GRIK1 inhibited the proliferation, colony formation, migration, invasion and epithelial-mesenchymal transition of HCT116 cells in vitro. In contrast, the genetic knockdown of GRIK1 promoted the proliferative, colony forming, migratory and invasive abilities of SW620 cells in vitro. Moreover, the overexpression of GRIK1 inhibited tumor growth, and liver and lung metastasis of CRC in vivo. In conclusion, the findings of the present study suggested that GRIK1 may serve as a tumor suppressor in CRC, and upregulated expression levels of GRIK1 may predict an improved prognosis for patients with CRC.
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Affiliation(s)
- Zhong Ren
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jingzheng Liu
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Liqing Yao
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jian Li
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhipeng Qi
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Bing Li
- Endoscopy Research Institute, Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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IgE Antibodies against Cancer: Efficacy and Safety. Antibodies (Basel) 2020; 9:antib9040055. [PMID: 33081206 PMCID: PMC7709114 DOI: 10.3390/antib9040055] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 09/25/2020] [Accepted: 10/09/2020] [Indexed: 12/13/2022] Open
Abstract
Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to the rise of a new class of therapeutic antibodies to complement the armamentarium of approved tumour targeting antibodies, which to date are all IgG class. The perceived risk of type I hypersensitivity reactions following administration of IgE has necessitated particular consideration in the development of these therapeutic agents. Here, we bring together the properties of IgE antibodies pivotal to the hypothesis for superior antitumour activity compared to IgG, observations of in vitro and in vivo efficacy and mechanisms of action, and a focus on the safety considerations for this novel class of therapeutic agent. These include in vitro studies of potential hypersensitivity, selection of and observations from appropriate in vivo animal models and possible implications of the high degree of glycosylation of IgE. We also discuss the use of ex vivo predictive and monitoring clinical tools, as well as the risk mitigation steps employed in, and the preliminary outcomes from, the first-in-human clinical trial of a candidate anticancer IgE therapeutic.
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Marone G, Schroeder JT, Mattei F, Loffredo S, Gambardella AR, Poto R, de Paulis A, Schiavoni G, Varricchi G. Is There a Role for Basophils in Cancer? Front Immunol 2020; 11:2103. [PMID: 33013885 PMCID: PMC7505934 DOI: 10.3389/fimmu.2020.02103] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 08/03/2020] [Indexed: 12/11/2022] Open
Abstract
Basophils were identified in human peripheral blood by Paul Ehrlich over 140 years ago. Human basophils represent <1% of peripheral blood leukocytes. During the last decades, basophils have been described also in mice, guinea pigs, rabbits, and monkeys. There are many similarities, but also several immunological differences between human and mouse basophils. There are currently several strains of mice with profound constitutive or inducible basophil deficiency useful to prove that these cells have specific roles in vivo. However, none of these mice are solely and completely devoid of all basophils. Therefore, the relevance of these findings to humans remains to be established. It has been known for some time that basophils have the propensity to migrate into the site of inflammation. Recent observations indicate that tissue resident basophils contribute to lung development and locally promote M2 polarization of macrophages. Moreover, there is increasing evidence that lung-resident basophils exhibit a specific phenotype, different from circulating basophils. Activated human and mouse basophils synthesize restricted and distinct profiles of cytokines. Human basophils produce several canonical (e.g., VEGFs, angiopoietin 1) and non-canonical (i.e., cysteinyl leukotriene C4) angiogenic factors. Activated human and mouse basophils release extracellular DNA traps that may have multiple effects in cancer. Hyperresponsiveness of basophils has been demonstrated in patients with JAK2V617F-positive polycythemia vera. Basophils are present in the immune landscape of human lung adenocarcinoma and pancreatic cancer and can promote inflammation-driven skin tumor growth. The few studies conducted thus far using different models of basophil-deficient mice have provided informative results on the roles of these cells in tumorigenesis. Much more remains to be discovered before we unravel the hitherto mysterious roles of basophils in human and experimental cancers.
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Affiliation(s)
- Giancarlo Marone
- Section of Hygiene, Department of Public Health, University of Naples Federico II, Naples, Italy.,Azienda Ospedaliera Ospedali dei Colli, Monaldi Hospital Pharmacy, Naples, Italy
| | - John T Schroeder
- Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD, United States
| | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Naples, Italy
| | | | - Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Naples, Italy
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Bax HJ, Chauhan J, Stavraka C, Khiabany A, Nakamura M, Pellizzari G, Ilieva KM, Lombardi S, Gould HJ, Corrigan CJ, Till SJ, Katugampola S, Jones PS, Barton C, Winship A, Ghosh S, Montes A, Josephs DH, Spicer JF, Karagiannis SN. Basophils from Cancer Patients Respond to Immune Stimuli and Predict Clinical Outcome. Cells 2020; 9:E1631. [PMID: 32645919 PMCID: PMC7408103 DOI: 10.3390/cells9071631] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023] Open
Abstract
Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation (n = 35), and gene signatures indicating the presence of activated basophils in tumors (n = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology.
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Affiliation(s)
- Heather J. Bax
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
| | - Jitesh Chauhan
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
| | - Chara Stavraka
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - Atousa Khiabany
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
| | - Mano Nakamura
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
| | - Giulia Pellizzari
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
| | - Kristina M. Ilieva
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London SE1 9RT, UK
| | - Sara Lombardi
- Guy’s and St Thomas’ Oncology & Haematology Clinical Trials (OHCT), Guy’s Cancer Centre, London SE1 9RT, UK;
| | - Hannah J. Gould
- Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London, London SE1 9RT, UK;
- Asthma UK Centre, Allergic Mechanisms in Asthma, King’s College London, London SE1 9RT, UK; (C.J.C.); (S.J.T.)
| | - Christopher J. Corrigan
- Asthma UK Centre, Allergic Mechanisms in Asthma, King’s College London, London SE1 9RT, UK; (C.J.C.); (S.J.T.)
- Department of Respiratory Medicine and Allergy and School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK
| | - Stephen J. Till
- Asthma UK Centre, Allergic Mechanisms in Asthma, King’s College London, London SE1 9RT, UK; (C.J.C.); (S.J.T.)
- Department of Respiratory Medicine and Allergy and School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK
| | - Sidath Katugampola
- Centre for Drug Development, Cancer Research UK, 2 Redman Place, London E20 1JQ, UK; (S.K.); (P.S.J.); (C.B.)
| | - Paul S. Jones
- Centre for Drug Development, Cancer Research UK, 2 Redman Place, London E20 1JQ, UK; (S.K.); (P.S.J.); (C.B.)
| | - Claire Barton
- Centre for Drug Development, Cancer Research UK, 2 Redman Place, London E20 1JQ, UK; (S.K.); (P.S.J.); (C.B.)
- Barton Oncology Ltd., 8 Elm Avenue, Eastcote, Middlesex HA4 8PD, UK
| | - Anna Winship
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - Sharmistha Ghosh
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - Ana Montes
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - Debra H. Josephs
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - James F. Spicer
- School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
- Departments of Medical Oncology and Clinical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 9RT, UK; (A.W.); (S.G.); (A.M.)
| | - Sophia N. Karagiannis
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, London SE1 9RT, UK; (H.J.B.); (J.C.); (C.S.); (A.K.); (M.N.); (G.P.); (K.M.I.); (D.H.J.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London SE1 9RT, UK
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Khan ANH, Emmons TR, Wong JT, Alqassim E, Singel KL, Mark J, Smith BE, Tario JD, Eng KH, Moysich KB, Odunsi K, Abrams SI, Segal BH. Quantification of Early-Stage Myeloid-Derived Suppressor Cells in Cancer Requires Excluding Basophils. Cancer Immunol Res 2020; 8:819-828. [PMID: 32238380 PMCID: PMC7269807 DOI: 10.1158/2326-6066.cir-19-0556] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 01/17/2020] [Accepted: 03/25/2020] [Indexed: 12/20/2022]
Abstract
Myeloid derived suppressor cells (MDSC) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. On the basis of surface markers, three subsets of MDSCs have been defined in humans: granulocytic, monocytic, and early stage (e-MDSC). The markers attributed to e-MDSCs overlap with those of basophils, which are rare circulating myeloid cells with unrecognized roles in cancer. Thus, we asked whether e-MDSCs in circulation and the tumor microenvironment include basophils. On average, 58% of cells with e-MDSC surface markers in blood and 36% in ascites from patients with ovarian cancer were basophils based on CD123high expression and cytology, whereas cells with immature features were rare. Circulating and ascites basophils did not suppress proliferation of stimulated T cells, a key feature of MDSCs. Increased accumulation of basophils and basogranulin, a marker of basophil degranulation, were observed in ascites compared to serum in patients with newly diagnosed ovarian cancer. Basophils recruited to the tumor microenvironment may exacerbate fluid accumulation by their release of proinflammatory granular constituents that promote vascular leakage. No significant correlation was observed between peripheral basophil counts and survival in patients with ovarian cancer. Our results suggest that studies in which e-MDSCs were defined solely by surface markers should be reevaluated to exclude basophils. Both immaturity and suppression are criteria to define e-MDSCs in future studies.
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Affiliation(s)
- Anm Nazmul H Khan
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Tiffany R Emmons
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Jerry T Wong
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Emad Alqassim
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kelly L Singel
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Jaron Mark
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Brandon E Smith
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Joseph D Tario
- Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kevin H Eng
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kirsten B Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kunle Odunsi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Brahm H Segal
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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Liu Q, Luo D, Cai S, Li Q, Li X. Circulating basophil count as a prognostic marker of tumor aggressiveness and survival outcomes in colorectal cancer. Clin Transl Med 2020; 9:6. [PMID: 32037496 PMCID: PMC7008108 DOI: 10.1186/s40169-019-0255-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 12/26/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Accumulating evidence demonstrated immune/inflammation-related implications of basophils in affecting tissue microenvironment that surrounded a tumor, and this study aimed to elucidate the clinical value of serum basophil count level. METHODS Between December 2007 and September 2013, 1029 patients diagnosed with stage I-III CRC in Fudan University Shanghai Cancer Center meeting the essential criteria were identified. The Kaplan-Meier method was used to construct the survival curves. Several Cox proportional hazard models were constructed to assess the prognostic factors. A simple predictor (CB classifier) was generated by combining serum basophil count and serum carcinoembryonic antigen (CEA) level which had long been accepted as the most important and reliable prognostic factor in CRC. RESULTS The preoperative basophils count < 0.025*109/L was strongly associated with higher T stage, higher N stage, venous invasion, perineural invasion, elevated serum CEA level, and thus poor survival (P < 0.05). Moreover, multivariate Cox analysis showed that patients with low level of preoperative basophils count had an evidently poorer DFS [Hazard ratio (HR) = 2.197, 95% CI 1.868-2.585]. CONCLUSIONS As a common immune/inflammation-related biomarker available from the blood routine examination, low level of preoperative serum basophil count was associated with aggressive biology and indicated evidently poor survival. Preoperative serum basophil count would be a useful and simple marker for the management of CRC patients.
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Affiliation(s)
- Qi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dakui Luo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, #270 Dongan Road, Xuhui District, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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46
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Marone G, Gambardella AR, Mattei F, Mancini J, Schiavoni G, Varricchi G. Basophils in Tumor Microenvironment and Surroundings. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1224:21-34. [PMID: 32036602 DOI: 10.1007/978-3-030-35723-8_2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Basophils represent approximately 1% of human peripheral blood leukocytes. Their effector functions were initially appreciated in the 1970s when basophils were shown to express the high-affinity receptor (FcεRI) for IgE and to release proinflammatory mediators (histamine and cysteinyl leukotriene C4) and immunoregulatory cytokines (i.e., IL-4 and IL-13). Basophils in the mouse were subsequently identified and immunologically characterized. There are many similarities but also several differences between human and mouse basophils. Basophil-deficient mice have enabled to examine the in vivo roles of basophils in several immune disorders and, more recently, in tumor immunity. Activated human basophils release several proangiogenic molecules such as vascular endothelial growth factor-A (VEGF-A), vascular endothelial growth factor-B (VEGF-B), CXCL8, angiopoietin 1 (ANGPT1), and hepatocyte growth factor (HGF). On the other side, basophils can exert anti-tumorigenic effects by releasing granzyme B, TNF-α, and histamine. Circulating basophils have been associated with certain human hematologic (i.e., chronic myeloid leukemia) and solid tumors. Basophils have been found in tumor microenvironment (TME) of human lung adenocarcinoma and pancreatic cancer. Basophils played a role in melanoma rejection in basophil-deficient mouse model. By contrast, basophils appear to play a pro-tumorigenic role in experimental and human pancreatic cancer. In conclusion, the roles of basophils in experimental and human cancers have been little investigated and remain largely unknown. The elucidation of the roles of basophils in tumor immunity will demand studies on increasing complexity beyond those assessing basophil density and their microlocalization in TME. There are several fundamental questions to be addressed in experimental models and clinical studies before we understand whether basophils are an ally, adversary, or even innocent bystanders in cancers.
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Affiliation(s)
- Giancarlo Marone
- Department of Public Health, University of Naples Federico II, Naples, Italy
- Azienda Ospedaliera dei Colli-Monaldi Hospital Pharmacy, Naples, Italy
| | | | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Jacopo Mancini
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
- WAO Center of Excellence, Naples, Italy.
- Institute of Experimental Endocrinology and Oncology "G. Salvatore" (IEOS), National Research Council (CNR), Naples, Italy.
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Overview of Basic Immunology and Clinical Application. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:1-36. [PMID: 32301008 DOI: 10.1007/978-3-030-41008-7_1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
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Zhang YY, Li WQ, Li ZF, Guo XH, Zhou SK, Lin A, Yan WH. Higher Levels of Pre-operative Peripheral Lymphocyte Count Is a Favorable Prognostic Factor for Patients With Stage I and II Rectal Cancer. Front Oncol 2019; 9:960. [PMID: 31612109 PMCID: PMC6769073 DOI: 10.3389/fonc.2019.00960] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/10/2019] [Indexed: 12/13/2022] Open
Abstract
The clinical significance of peripheral blood parameters has been considered to be a potential prognostic indicator for malignancies. In this study, 224 colorectal cancer (CRC; ncolon = 103; nrectal = 121) patients who underwent resection were enrolled, and the pre- and post-operative clinical laboratory data within 1 week, before and after surgery, were collected. The prognostic value of the counts of white blood cell (WBC), neutrophil, lymphocyte and platelet, the neutrophil to lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) were analyzed. Data revealed that pre-operative lymphocyte count (pre-LC) was much higher than that of post-LC (p < 0.001), and only rectal cancer patients with pre-LChigh (>median: 1.61 × 109/L) had a significantly better overall survival (OS) and 5-year survival rate (SR) than those with pre-LClow (OS: 62.3 vs. 49.5 months; SR: 74.0 vs. 43.0%; p = 0.006). Cox's proportional hazard models revealed that pre-LChigh was an independent, favorable prognostic factor for rectal cancer patients (hazard ratio = 0.348; p = 0.003). Moreover, when the disease stages were stratified, the pre-LChigh was significantly associated with better prognosis of rectal cancer patients with stage I + II rectal cancer (n = 65; OS: 67.5 vs. 54.3 months; p = 0.011). Taken together, our study revealed that pre-operative lymphocyte count is an independent prognostic factor for patients with stage I and II rectal cancer.
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Affiliation(s)
- Ying-Ying Zhang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wan-Qing Li
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhen-Fa Li
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiao-Hua Guo
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shen-Kang Zhou
- Department of Gastrointestinal Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Aifen Lin
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wei-Hua Yan
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
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Loktionov A. Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders. World J Gastroenterol 2019; 25:3503-3526. [PMID: 31367153 PMCID: PMC6658389 DOI: 10.3748/wjg.v25.i27.3503] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/22/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are currently regarded as versatile mobile cells controlling and regulating multiple biological pathways and responses in health and disease. These cells store in their specific granules numerous biologically active substances (cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes) ready for rapid release. The human gut is the main destination of eosinophils that are produced and matured in the bone marrow and then transferred to target tissues through the circulation. In health the most important functions of gut-residing eosinophils comprise their participation in the maintenance of the protective mucosal barrier and interactions with other immune cells in providing immunity to microbiota of the gut lumen. Eosinophils are closely involved in the development of inflammatory bowel disease (IBD), when their cytotoxic granule proteins cause damage to host tissues. However, their roles in Crohn's disease and ulcerative colitis appear to follow different immune response patterns. Eosinophils in IBD are especially important in altering the structure and protective functions of the mucosal barrier and modulating massive neutrophil influx to the lamina propria followed by transepithelial migration to colorectal mucus. IBD-associated inflammatory process involving eosinophils then appears to expand to the mucus overlaying the internal gut surface. The author hypothesises that immune responses within colorectal mucus as well as ETosis exerted by both neutrophils and eosinophils on the both sides of the colonic epithelial barrier act as additional pathogenetic factors in IBD. Literature analysis also shows an association between elevated eosinophil levels and better colorectal cancer (CRC) prognosis, but mechanisms behind this effect remain to be elucidated. In conclusion, the author emphasises the importance of investigating colorectal mucus in IBD and CRC patients as a previously unexplored milieu of disease-related inflammatory responses.
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50
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Simon SCS, Utikal J, Umansky V. Opposing roles of eosinophils in cancer. Cancer Immunol Immunother 2019; 68:823-833. [PMID: 30302498 PMCID: PMC11028063 DOI: 10.1007/s00262-018-2255-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 09/28/2018] [Indexed: 12/13/2022]
Abstract
Eosinophils are a subset of granulocytes mostly known for their ability to combat parasites and induce allergy. Although they were described to be related to cancer more than 100 years ago, their role in tumors is still undefined. Recent observations revealed that they display regulatory functions towards other immune cell subsets in the tumor microenvironment or direct cytotoxic functions against tumor cells, leading to either antitumor or protumor effects. This paradoxical role of eosinophils was suggested to be dependent on the different factors in the TME. In addition, the clinical relevance of these cells has been recently addressed. In most cases, the accumulation of eosinophils both in the tumor tissue, called tumor-associated tissue eosinophilia, and in the peripheral blood were reported to be prognostic markers for a better outcome of cancer patients. In immunotherapy of cancer, particularly in therapy with immune checkpoint inhibitors, eosinophils were even shown to be a potential predictive marker for a beneficial clinical response. A better understanding of their role in cancer progression will help to establish them as prognostic and predictive markers and to design strategies for targeting eosinophils.
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Affiliation(s)
- Sonja C S Simon
- Skin Cancer Unit, Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, Clinical Cooperation Unit Dermato-Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
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