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Xu J, Gao H, Azhar MS, Xu H, Chen S, Li M, Ni X, Yan T, Zhou H, Long Q, Yi W. Interleukin signaling in the regulation of natural killer cells biology in breast cancer. Front Immunol 2024; 15:1449441. [PMID: 39380989 PMCID: PMC11459090 DOI: 10.3389/fimmu.2024.1449441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 09/09/2024] [Indexed: 10/10/2024] Open
Abstract
In the field of breast cancer treatment, the immunotherapy involving natural killer (NK) cells is increasingly highlighting its distinct potential and significance. Members of the interleukin (IL) family play pivotal regulatory roles in the growth, differentiation, survival, and apoptosis of NK cells, and are central to their anti-tumor activity. These cytokines enhance the ability of NK cells to recognize and eliminate tumor cells by binding to specific receptors and activating downstream signaling pathways. Furthermore, interleukins do not function in isolation; the synergistic or antagonistic interactions between different interleukins can drive NK cells toward various functional pathways, ultimately leading to diverse outcomes for breast cancer patients. This paper reviews the intricate relationship between NK cells and interleukins, particularly within the breast cancer tumor microenvironment. Additionally, we summarize the latest clinical studies and advancements in NK cell therapy for breast cancer, along with the potential applications of interleukin signaling in these therapies. In conclusion, this article underscores the critical role of NK cells and interleukin signaling in breast cancer treatment, providing valuable insights and a significant reference for future research and clinical practice.
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Affiliation(s)
- Jiachi Xu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center For Breast Disease In Hunan Province, Changsha, Hunan, China
| | - Hongyu Gao
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center For Breast Disease In Hunan Province, Changsha, Hunan, China
| | - Muhammad Salman Azhar
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haifan Xu
- Breast and Thyroid Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Siyuan Chen
- Breast and Thyroid Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Mingcan Li
- Breast and Thyroid Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Xinxi Ni
- Breast and Thyroid Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Ting Yan
- Breast and Thyroid Surgery, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Hui Zhou
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Long
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center For Breast Disease In Hunan Province, Changsha, Hunan, China
| | - Wenjun Yi
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center For Breast Disease In Hunan Province, Changsha, Hunan, China
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Hunzeker ZE, Zhao L, Kim AM, Parker JM, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The role of IL-22 in cancer. Med Oncol 2024; 41:240. [PMID: 39231878 DOI: 10.1007/s12032-024-02481-8] [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: 06/23/2024] [Accepted: 08/16/2024] [Indexed: 09/06/2024]
Abstract
Interleukin-22, discovered in the year of 2000, is a pleiotropic Th17 cytokine from the IL-10 family of cytokines. IL-22 signals through the type 2 cytokine receptor complex IL-22R and predominantly activates STAT3. This pathway leads to the transcription of several different types of genes, giving IL-22 context-specific functions ranging from inducing antimicrobial peptide expression to target cell proliferation. In recent years, it has been shown that IL-22 is involved in the pathogenesis of neoplasia in some cancers through its pro-proliferative and anti-apoptotic effects. This review highlights studies with recent discoveries and conclusions drawn on IL-22 and its involvement and function in various cancers. Such a study may be helpful to better understand the role of IL-22 in cancer so that new treatment could be developed targeting IL-22.
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Affiliation(s)
- Zachary E Hunzeker
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Department of Internal Medicine, University of Texas Houston Health Science Center, Houston, TX, USA
| | - Lei Zhao
- Department of Respiratory Medicine, the 2nd People's Hospital of Hefei and Hefei Hospital Affiliated to Anhui Medical University, Hefei, China
| | - Austin M Kim
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
| | - Jacob M Parker
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
| | - Ziwen Zhu
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Huaping Xiao
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Qian Bai
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines, IA, 50312, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
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Ogbodo AK, Mustafov D, Arora M, Lambrou GI, Braoudaki M, Siddiqui SS. Analysis of SIGLEC12 expression, immunomodulation and prognostic value in renal cancer using multiomic databases. Heliyon 2024; 10:e24286. [PMID: 38268823 PMCID: PMC10803920 DOI: 10.1016/j.heliyon.2024.e24286] [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: 06/04/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/26/2024] Open
Abstract
Siglecs belong to a family of immune regulatory receptors predominantly found on hematopoietic cells. They interact with Sia, resulting in the activation or inhibition of the immune response. Previous reports have suggested that the SIGLEC12 gene, which encodes the Siglec-XII protein, is expressed in the epithelial tissues and upregulated in carcinomas. However, studies deciphering the role of Siglec-XII in renal cancer (RC) are still unavailable, and here we provide insights on this question. We conducted expression analysis using the Human Protein Atlas and UALCAN databases. The impact of SIGLEC12 on RC prognosis was determined using the KM plotter, and an assessment of immune infiltration with SIGLEC12 was performed using the TIMER database. GSEA was conducted to identify the pathways affected by SIGLEC12. Finally, using GeneMania, we identified Siglec-XII interacting proteins. Our findings indicated that macrophages express SIGLEC12 in the kidney. Furthermore, we hypothesize that Siglec-XII expression might be involved in the increase of primary RC, but this effect may not be dependent on the age of the patient. In the tumour microenvironment, oncogenic pathways appeared to be upregulated by SIGLEC12. Similarly, our analysis suggested that SIGLEC12-related kidney renal papillary cell carcinomas may be more suitable for targeted immunotherapy, such as CTLA-4 and PD-1/PD-L1 inhibitors. These preliminary results suggested that high expression of SIGLEC12 is associated with poor prognosis for RC. Future studies to assess its clinical utility are necessitated.
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Affiliation(s)
- Amobichukwu K. Ogbodo
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
- #Current Address: Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, United Kingdom
| | - Denis Mustafov
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
- College of Health, Medicine, and Life Science, Brunel University London UB8 3PH, United Kingdom
| | - Mohit Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - George I. Lambrou
- Choremeio Research Laboratory, First Department of Paediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, Thivon & Levadeias 8, 11527, Goudi, Athens, Greece
- University Research Institute of Maternal and Child Health & Precision Medicine, National and Kapodistrian University of Athens, Thivon & Levadeias 8, 11527 Athens, Greece
| | - Maria Braoudaki
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
| | - Shoib S. Siddiqui
- School of Life and Medical Sciences, University of Hertfordshire, College Lane Campus, Hatfield AL10 9AB, United Kingdom
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Peng Z, Dong X, He M, Zhao Y, Liu Y, Li M, Li G, Wang X, Li L, Hu Y. Elevated profiles of peripheral Th22, Th17, Th2 cells, and decreased percentage of Th1 cells in breast cancer patients. Thorac Cancer 2023; 14:3282-3294. [PMID: 37732365 PMCID: PMC10665788 DOI: 10.1111/1759-7714.15119] [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: 07/23/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Th22 subset is a particular type of CD4+ T helper cells subset. Our study aimed to explore the expression level of circulating Th22, Th17, Th1, and Th2 cells and the possible mechanism of these cells in breast cancer (BC) with different pathological features. METHODS Our study enrolled 43 newly diagnosed BC patients and 30 healthy controls. Frequencies of peripheral Th22, Th17, Th1, and Th2 cells were tested by flow cytometry. Concentrations of IL-22 cytokine in plasma were examined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was done to test aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) gene expression. RESULTS Frequencies of Th22, Th17, Th2 subsets, and the plasma IL-22 level was obviously higher in the BC patients. A positive correlation between Th22 frequency and IL-22 concentration in plasma was detected in BC patients. Furthermore, the percentage of Th22, Th2 subsets in peripheral blood of HER2 positive BC was higher than that in HER2 negative BC patients. A negative correlation between Th1 subset and Ki-67% as well as a positive correlation between Th2 subset and Ki-67% was found in BC patients. The proportion of Th1 cells in BC patients was significantly lower than that of the control group. Expression of AHR and RORC transcription factors were also observed to be upregulated in the BC patients. Furthermore, Th22 cells were positively correlated with BC tumor stage and clinical outcomes. The BC patients with a higher percentage of Th22, Th17, Th1 cells or a lower percentage of Th1 cells showed a decreased trend of survival rate. CONCLUSION Th22, Th17, Th1, and Th2 subsets may play an essential role in BC patients. Th22, Th17, Th1, and Th2 cells may have potential significance to be used as clinical markers in BC patients with different molecular classification. Th22 cells may have potential value in BC patients' outcomes prediction, providing clinical value.
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Affiliation(s)
- Zhiguo Peng
- Department of Organ Transplantation, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xinyue Dong
- Department of OncologyQilu Hospital of Shandong University Dezhou HospitalDezhouChina
| | - Miao He
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yajing Zhao
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yujia Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Mo Li
- Department of OncologyWeifang People's HospitalWeifangChina
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Xiuwen Wang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Li Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Yu Hu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanChina
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Zou X, Guan C, Gao J, Shi W, Cui Y, Zhong X. Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy. Front Immunol 2023; 14:1222719. [PMID: 37529035 PMCID: PMC10388371 DOI: 10.3389/fimmu.2023.1222719] [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: 05/15/2023] [Accepted: 06/26/2023] [Indexed: 08/03/2023] Open
Abstract
Pancreatic cancer (PC) is extremely malignant and shows limited response to available immunotherapies due to the hypoxic and immunosuppressive nature of its tumor microenvironment (TME). The aggregation of immune cells (B cells, T cells, dendritic cells, etc.), which is induced in various chronic inflammatory settings such as infection, inflammation, and tumors, is known as the tertiary lymphoid structure (TLS). Several studies have shown that TLSs can be found in both intra- and peritumor tissues of PC. The role of TLSs in peritumor tissues in tumors remains unclear, though intratumoral TLSs are known to play an active role in a variety of tumors, including PC. The formation of intratumoral TLSs in PC is associated with a good prognosis. In addition, TLSs can be used as an indicator to assess the effectiveness of treatment. Targeted induction of TLS formation may become a new avenue of immunotherapy for PC. This review summarizes the formation, characteristics, relevant clinical outcomes, and clinical applications of TLSs in the pancreatic TME. We aim to provide new ideas for future immunotherapy of PC.
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Affiliation(s)
- Xinlei Zou
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Canghai Guan
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jianjun Gao
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wujiang Shi
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunfu Cui
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiary Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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Briukhovetska D, Suarez-Gosalvez J, Voigt C, Markota A, Giannou AD, Schübel M, Jobst J, Zhang T, Dörr J, Märkl F, Majed L, Müller PJ, May P, Gottschlich A, Tokarew N, Lücke J, Oner A, Schwerdtfeger M, Andreu-Sanz D, Grünmeier R, Seifert M, Michaelides S, Hristov M, König LM, Cadilha BL, Mikhaylov O, Anders HJ, Rothenfusser S, Flavell RA, Cerezo-Wallis D, Tejedo C, Soengas MS, Bald T, Huber S, Endres S, Kobold S. T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis. Immunity 2023; 56:143-161.e11. [PMID: 36630913 PMCID: PMC9839367 DOI: 10.1016/j.immuni.2022.12.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/28/2022] [Accepted: 12/13/2022] [Indexed: 01/12/2023]
Abstract
Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.
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Affiliation(s)
- Daria Briukhovetska
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Javier Suarez-Gosalvez
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Cornelia Voigt
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Anamarija Markota
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Anastasios D. Giannou
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, and Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany,Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Maryam Schübel
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Jakob Jobst
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Tao Zhang
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, and Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Janina Dörr
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Florian Märkl
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Lina Majed
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Philipp Jie Müller
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Peter May
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Adrian Gottschlich
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Nicholas Tokarew
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Jöran Lücke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, and Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany,Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Arman Oner
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Melanie Schwerdtfeger
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - David Andreu-Sanz
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Ruth Grünmeier
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Matthias Seifert
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Stefanos Michaelides
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Michael Hristov
- Institute for Cardiovascular Prevention (IPEK), University Hospital, Klinikum der Universität München, Munich, Germany
| | - Lars M. König
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | - Bruno Loureiro Cadilha
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany
| | | | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Klinikum der Universität München, 80337 Munich, Germany
| | - Simon Rothenfusser
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany,Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
| | - Richard A. Flavell
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA,Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Daniela Cerezo-Wallis
- Melanoma Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Cristina Tejedo
- Melanoma Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - María S. Soengas
- Melanoma Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
| | - Tobias Bald
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Samuel Huber
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, and Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Stefan Endres
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany,Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany,Center for Translational Cancer Research (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Klinikum der Universität München, 80337 Munich, Germany; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany; Center for Translational Cancer Research (DKTK), Partner Site Munich, 80336 Munich, Germany.
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7
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Bartolini I, Nannini G, Risaliti M, Matarazzo F, Moraldi L, Ringressi MN, Taddei A, Amedei A. Impact of microbiota-immunity axis in pancreatic cancer management. World J Gastroenterol 2022; 28:4527-4539. [PMID: 36157926 PMCID: PMC9476869 DOI: 10.3748/wjg.v28.i32.4527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/28/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
The microbiota impact on human diseases is well-known, and a growing body of literature is providing evidence about the complex interplay between microbiota-immune system-human physiology/pathology, including cancers. Together with the defined risk factors (e.g., smoke habits, diet, diabetes, and obesity), the oral, gut, biliary, and intrapancreatic microbiota contribute to pancreatic cancer development through different pathways including the interaction with the immune system. Unfortunately, a great majority of the pancreatic cancer patients received a diagnosis in advanced stages not amenable to be radically treated and potentially cured. Given the poor pancreatic cancer prognosis, complete knowledge of these complicated relationships could help researchers better understand the disease pathogenesis and thus provide early potential non-invasive biomarkers, new therapeutic targets, and tools for risk stratification that might result in greater therapeutic possibilities and eventually in a better and longer patient survival.
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Affiliation(s)
- Ilenia Bartolini
- Department of Experimental and Clinical Medicine, HPB Surgery Unit, Azienda Ospedaliero-Universitaria Careggi, Florence 50134, Italy
| | - Giulia Nannini
- Department of Experimental and Clinical Medicine, SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera-Universitaria Careggi, Florence 50134, Italy
| | - Matteo Risaliti
- Department of Experimental and Clinical Medicine, HPB Surgery Unit, Azienda Ospedaliero-Universitaria Careggi, Florence 50134, Italy
| | - Francesco Matarazzo
- Department of Experimental and Clinical Medicine, HPB Surgery Unit, Azienda Ospedaliero-Universitaria Careggi, Florence 50134, Italy
| | - Luca Moraldi
- Division of Oncologic Surgery, Department of Oncology, Careggi University Hospital, Firenze 50134, Italy
| | - Maria Novella Ringressi
- Department of Experimental and Clinical Medicine, HPB Surgery Unit, Azienda Ospedaliero-Universitaria Careggi, Florence 50134, Italy
| | - Antonio Taddei
- Department of Experimental and Clinical Medicine, HPB Surgery Unit, Azienda Ospedaliero-Universitaria Careggi, Florence 50134, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera-Universitaria Careggi, Florence 50134, Italy
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8
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Dai L, Mugaanyi J, Cai X, Lu C, Lu C. Pancreatic adenocarcinoma associated immune-gene signature as a novo risk factor for clinical prognosis prediction in hepatocellular carcinoma. Sci Rep 2022; 12:11944. [PMID: 35831362 PMCID: PMC9279485 DOI: 10.1038/s41598-022-16155-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022] Open
Abstract
Pancreatic adenocarcinoma (PAAD) has high mortality and a very poor prognosis. Both surgery and chemotherapy have a suboptimal therapeutic effect, and this caused a need to find new approaches such as immunotherapy. Therefore, it is essential to develop a new model to predict patient prognosis and facilitate early intervention. Our study screened out and validated the target molecules based on the TCGA-PAAD dataset. We established the risk signature using univariate and multivariate Cox regression analysis and used GSE62452 and GSE28735 to verify the accuracy and reliability of the model. Expanded application of PAAD-immune-related genes signature (-IRGS) on other datasets was conducted, and the corresponding nomograms were constructed. We also analyzed the correlation between immune-related cells/genes and potential treatments. Our research demonstrated that a high riskscore of PAAD-IRGS in patients with PAAD was correlated with poor overall survival, disease-specific survival and progression free interval. The same results were observed in patients with LIHC. The models constructed were confirmed to be accurate and reliable. We found various correlations between PAAD-IRGS and immune-related cells/genes, and the potential therapeutic agents. These findings indicate that PAAD-IRGS may be a promising indicator for prognosis and of the tumor-immune microenvironment status in PAAD.
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Affiliation(s)
- Lei Dai
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Joseph Mugaanyi
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Xingchen Cai
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China
| | - Caide Lu
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China.
| | - Changjiang Lu
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 1111 Jiangnan Road, Ningbo, 315040, Zhejiang, China.
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9
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Zhang J, Liu Z, Liu L, Huang M, Huang Y. Th22/IL-22 mediates the progression of HBV-related hepatocellular carcinoma via STAT3. Cytotechnology 2022; 74:203-216. [PMID: 35464167 PMCID: PMC8975974 DOI: 10.1007/s10616-021-00517-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022] Open
Abstract
T helper cell 22 are abundant in Hepatitis B Virus-related hepatocellular carcinoma tissue, and the main cytokine interleukin 22 produced by Th22 cells is closely related to the initiation and development of HCC. Understanding the role of Th22/IL-22 in the progression of HBV-related HCC will facilitate new therapeutic development. Th22 cells were isolated from peripheral blood of healthy donors and co-cultured with HBV positive HepG2.2.15 cells. IL-22 secretion and HepG2.2.15 cell proliferation and apoptosis were monitored. Expressions of p-STAT3, Cyclin D1, Bcl-2, and cleaved caspase 3 were detected by Western blot analysis. Th22 cells significantly promoted the proliferation and inhibited the apoptosis of HepG2.2.15 cells; up-regulated expression of p-STAT3, Cyclin D1 and Bcl-2, and down-regulated cleaved caspase 3 in HepG2.2.15 cells. These effects were significantly attenuated when IL-22 and STAT3 was knockdown in Th22 and HepG2.2.15 cells, respectively. Our data suggests that HBV induces host Th22 cells to overexpress IL-22, which in turn triggers over-activation of STAT3 and its downstream signaling proteins to promote HCC progression. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-021-00517-9.
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Affiliation(s)
- Jia Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Zhou Liu
- Department of Internal Medicine, Jiangxi Provincial Chest Hospital, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Lingpeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Mingwen Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
| | - Yong Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006 People’s Republic of China
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10
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Zhu WJ, Hu ZF, Yuan Z. Progress in research of tumor infiltrating lymphocytes in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:1207-1214. [DOI: 10.11569/wcjd.v29.i21.1207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The 5-year survival rate of pancreatic cancer is less than 5%, and the only available treatments, surgery, chemotherapy, and chemoradiation, have shown limited effectiveness. Therefore, alternative treatment strategies are urgently needed. In recent years, tumor infiltrating lymphocyte (TIL) therapy has shown promising successes in the treatment of some types of solid tumors because of its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity. The significant association between a high TIL density in pancreatic cancer tissue and a good clinical outcome and success of pancreatic cancer-specific TIL expansion ex vivo potentiates the rationality of the TIL therapy in pancreatic cancer. However, there are still many challenges ahead, such as neoantigen screening, rapid cell expansion, and low cytotoxicity. This article reviews the recent advances and limitations of TIL therapy in pancreatic cancer and discusses its future directions.
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Affiliation(s)
- Wen-Jun Zhu
- CAR-T (Shanghai) Cell Biotechnology Co., Ltd, Shanghai 200433, China
| | - Zhan-Fei Hu
- CAR-T (Shanghai) Cell Biotechnology Co., Ltd, Shanghai 200433, China
| | - Zhou Yuan
- The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, China
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11
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Doulabi H, Masoumi E, Rastin M, Foolady Azarnaminy A, Esmaeili SA, Mahmoudi M. The role of Th22 cells, from tissue repair to cancer progression. Cytokine 2021; 149:155749. [PMID: 34739898 DOI: 10.1016/j.cyto.2021.155749] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/05/2021] [Accepted: 10/11/2021] [Indexed: 02/08/2023]
Abstract
CD4+ T helper (Th) cells play a significant role in modulating host defense. In the presence of lineage specific cytokine cocktail, Naive CD4+ T cells can differentiate into several categories with distinct cytokines profile and effector functions. Th22 cells are a recently identified subset of CD4+ T cell, which differentiate from Naive CD4+ T in the presence of IL-6 and TNF-α. Th22 characterized by the production of interleukin-22 (IL-22) and expression of aryl hydrocarbon receptor (AHR). The main function of Th22 cells is to participate in mucosal defense, tissue repair, and wound healing. However, controversial data have shown that overexpression of IL-22 can lead to pathological changes under inflammatory conditions and tumor progression. This review summarizes our knowledge about the role of Th22 and IL-22 cells in tumor progression through induction of inflammation.
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Affiliation(s)
- Hassan Doulabi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elham Masoumi
- Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran; Student Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Maryam Rastin
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Carpenter E, Nelson S, Bednar F, Cho C, Nathan H, Sahai V, di Magliano MP, Frankel TL. Immunotherapy for pancreatic ductal adenocarcinoma. J Surg Oncol 2021; 123:751-759. [PMID: 33595893 DOI: 10.1002/jso.26312] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer with an urgent need for better medical therapies. Efforts have been made to investigate the efficacy of immunotherapy, particularly given the hallmarks of immune suppression and exhaustion in PDAC tumors. Here, we review the molecular components responsible for the immune-privileged state in PDAC and provide an overview of the immunotherapeutic strategies for PDAC including vaccine therapy, checkpoint blockade, myeloid-targeted therapy, and immune agonist therapy.
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Affiliation(s)
- Eileen Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Sarah Nelson
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Clifford Cho
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Hari Nathan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Vaibhav Sahai
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Timothy L Frankel
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
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13
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Abstract
Worldwide, approximately half a million people are diagnosed with pancreatic cancer every year, with mortality rates of more than 90%. T cells within pancreatic tumors are generally infrequent and incapable of eliciting antitumor immunity. Thus, pancreatic cancer is considered an "immunologically cold" tumor. However, recent studies clearly show that when T-cell immunity in pancreatic cancer is sufficiently induced, T cells become effective weapons. This fact suggests that to improve pancreatic cancer patients' clinical outcomes, we need to unveil the complex immune biology of this disease. In this review, we discuss the elements of tumor immunogenicity in the specific context of pancreatic malignancy.
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14
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Pérez-Romero K, Rodríguez RM, Amedei A, Barceló-Coblijn G, Lopez DH. Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy. Int J Mol Sci 2020; 21:5521. [PMID: 32752264 PMCID: PMC7432816 DOI: 10.3390/ijms21155521] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/31/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
Integration of the tumor microenvironment as a fundamental part of the tumorigenic process has undoubtedly revolutionized our understanding of cancer biology. Increasing evidence indicates that neoplastic cells establish a dependency relationship with normal resident cells in the affected tissue and, furthermore, develop the ability to recruit new accessory cells that aid tumor development. In addition to normal stromal and tumor cells, this tumor ecosystem includes an infiltrated immune component that establishes complex interactions that have a critical effect during the natural history of the tumor. The process by which immune cells modulate tumor progression is known as immunoediting, a dynamic process that creates a selective pressure that finally leads to the generation of immune-resistant cells and the inability of the immune system to eradicate the tumor. In this context, the cellular and functional characterization of the immune compartment within the tumor microenvironment will help to understand tumor progression and, ultimately, will serve to create novel prognostic tools and improve patient stratification for cancer treatment. Here we review the impact of the immune system on tumor development, focusing particularly on its clinical implications and the current technologies used to analyze immune cell diversity within the tumor.
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Affiliation(s)
- Karim Pérez-Romero
- Lipids in Human Pathology, Health Research Institute of the Balearic Islands (IdISBa), Research Unit, University Hospital Son Espases, 07120 Palma, Spain; (K.P.-R.); (G.B.-C.)
| | - Ramón M. Rodríguez
- Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain;
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
- SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera Universitaria Careggi (AOUC), 50134 Florence, Italy
| | - Gwendolyn Barceló-Coblijn
- Lipids in Human Pathology, Health Research Institute of the Balearic Islands (IdISBa), Research Unit, University Hospital Son Espases, 07120 Palma, Spain; (K.P.-R.); (G.B.-C.)
| | - Daniel H. Lopez
- Lipids in Human Pathology, Health Research Institute of the Balearic Islands (IdISBa), Research Unit, University Hospital Son Espases, 07120 Palma, Spain; (K.P.-R.); (G.B.-C.)
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15
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Nannini G, Meoni G, Amedei A, Tenori L. Metabolomics profile in gastrointestinal cancers: Update and future perspectives. World J Gastroenterol 2020; 26:2514-2532. [PMID: 32523308 PMCID: PMC7265149 DOI: 10.3748/wjg.v26.i20.2514] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/11/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Despite recent progress in diagnosis and therapy, gastrointestinal (GI) cancers remain one of the most important causes of death with a poor prognosis due to late diagnosis. Serum tumor markers and detection of occult blood in the stool are the current tests used in the clinic of GI cancers; however, these tests are not useful as diagnostic screening since they have low specificity and low sensitivity. Considering that one of the hallmarks of cancer is dysregulated metabolism and metabolomics is an optimal approach to illustrate the metabolic mechanisms that belong to living systems, is now clear that this -omics could open a new way to study cancer. In the last years, nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for diseases' diagnosis nevertheless a few studies focus on the NMR capability to find new biomarkers for early diagnosis of GI cancers. For these reasons in this review, we will give an update on the status of NMR metabolomic studies for the diagnosis and development of GI cancers using biological fluids.
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Affiliation(s)
- Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gaia Meoni
- Giotto Biotech Srl, and CERM (University of Florence), Florence 50019, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Leonardo Tenori
- Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine, Florence 50019, Italy
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16
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Xuan X, Zhou J, Tian Z, Lin Y, Song J, Ruan Z, Ni B, Zhao H, Yang W. ILC3 cells promote the proliferation and invasion of pancreatic cancer cells through IL-22/AKT signaling. Clin Transl Oncol 2020; 22:563-575. [PMID: 31203574 DOI: 10.1007/s12094-019-02160-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 06/08/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE Type 3 innate lymphocytes (ILC3s) are reported to be involved in lung cancer, possibly by producing interleukin-22 (IL-22). However, whether ILC3s and their secreted IL-22 molecules contribute to the pathogenesis of pancreatic cancer (PC) remains unclear. To this end, in this study, we investigated the effects and possible mechanisms of ILC3s on PC pathogenesis. METHOD The IL-22 and IL-2i2R levels and the ILC3s' frequency in cancer tissues from PC patients and in peripheral blood from PC patients and healthy controls were analyzed by flow cytometry, immunochemistry, or immunofluorescence. The effects of IL-22-induced AKT signaling on the proliferation, invasion, and migration of PC cells were examined by co-culturing PC cell lines with ILC3s isolated from PC tissues, with or without the addition of neutralizing IL-22 antibody, IL-22R antibody or AKT inhibitor. RESULTS Our results showed that IL-22 and ILC3s were significantly upregulated in the PBMCs and cancer tissues of PC patients, and the IL-22R level was increased in PC cells. The increased frequency of ILC3s was positively correlated with the clinical features of PC patients. Co-culture experiments indicated that ILC3s promoted the proliferation, invasion, and migration of PC cell lines by secreting IL-22 to activate AKT signaling because IL-22/IL-22R or AKT blockage markedly counteracted such effects on PC cells. CONCLUSION Our data demonstrated that ILC3s may promote PC pathogenesis through IL-22/IL-22R-AKT signaling, suggesting a potential intervention target for PC treatment in the future.
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Affiliation(s)
- X Xuan
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, China
- Department of Kidney, Southwest Hospital, Army Medical University (Third Military Medical University), 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China
| | - J Zhou
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China
| | - Z Tian
- Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, China
| | - Y Lin
- Bellevue Christian High School, 1601 98th Ave NE, Bellevue, WA, 98004, USA
| | - J Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, TX, 77843, USA
| | - Z Ruan
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - B Ni
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, China.
| | - H Zhao
- Department of Kidney, Southwest Hospital, Army Medical University (Third Military Medical University), 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China.
| | - W Yang
- Department of Dermatology, The 181th Hospital of PLA, No. 1 Xinqiaoyuan Road, Guilin, 541002, Guangxi Zhuang Autonomous Region, China.
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17
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Illiano P, Brambilla R, Parolini C. The mutual interplay of gut microbiota, diet and human disease. FEBS J 2020; 287:833-855. [DOI: 10.1111/febs.15217] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/21/2019] [Accepted: 01/16/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Placido Illiano
- The Miami Project to Cure Paralysis Department of Neurological Surgery University of Miami Miller School of Medicine FL USA
| | - Roberta Brambilla
- The Miami Project to Cure Paralysis Department of Neurological Surgery University of Miami Miller School of Medicine FL USA
- Department of Neurobiology Research Institute of Molecular Medicine University of Southern Denmark Odense Denmark
- Department of Clinical Research BRIDGE‐Brain Research‐Inter‐Disciplinary Guided Excellence University of Southern Denmark Odense C Denmark
| | - Cinzia Parolini
- Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Italy
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18
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Yang XW, Jiang HX, Lei R, Lu WS, Tan SH, Qin SY. Recruitment and significance of Th22 cells and Th17 cells in malignant ascites. Oncol Lett 2018; 16:5389-5397. [PMID: 30250609 DOI: 10.3892/ol.2018.9316] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 09/01/2017] [Indexed: 01/10/2023] Open
Abstract
T helper (Th)22 and Th17 cells are implicated in the pathogenesis of a number of types of cancer. However, the function of Th22 and Th17 cells in malignant ascites (MA) remains unknown. The present study aimed at examining the distribution, phenotypes, recruitment, and prognostic value of Th22 and Th17 cells in MA from patients with hepatocellular carcinoma (HCC). A total of 26 patients with HCC with MA and 15 healthy controls were included in the present study. The proportion of Th22 cells, Th17 cells, C-C motif chemokine receptor (CCR)4, CCR6 and CCR10 were examined using flow cytometry. Interleukin (IL-)22, IL-17, C-C motif chemokine ligand (CCL)20, CCL22 and CCL27 were investigated using ELISA. In addition, the chemoattractant activity of chemokines for Th22 and Th17 cells in vitro were examined via a chemotaxis assay. The results of the present study demonstrated that Th22 cells, Th17 cells, IL-22 and IL-17 were significantly increased in MA compared with the corresponding blood and peripheral blood from healthy controls. Additionally, Th22 cells expressed increased concentrations of CCR6, CCR4 and CCR10, and Th17 cells expressed increased concentrations of CCR4 and CCR6 in MA compared with the corresponding blood. The chemotaxis assay revealed that CCL20/CCR6, CCL22/CCR4 and CCL27/CCR10 were responsible for the recruitment of Th22 cells into MA, whereas CCL22/CCR4 was responsible for the recruitment of Th17 cells. Furthermore, the patients with an increased number of Th17 cells exhibited an increased survival time compared with patients with a limited number of Th17 cells. Th22 and Th17 cells serve an important function in the development of MA, and the accumulation of Th22 and Th17 cells in MA may be due to a local increase in proinflammatory cytokines and chemokines. Increased Th17 cell numbers in MA may indicate the improvement of patient survival.
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Affiliation(s)
- Xian-Wen Yang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Hai-Xing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Ronge Lei
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Wei-Shun Lu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shi-Hui Tan
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shan-Yu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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19
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Pretherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio do not predict survival in resectable pancreatic cancer. HPB (Oxford) 2018; 20:398-404. [PMID: 29221789 DOI: 10.1016/j.hpb.2017.10.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/26/2017] [Accepted: 10/22/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pretherapy serum neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have both been identified as prognostic in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to identify the prognostic implication of pretherapy NLR and PLR in patients with resectable PDAC. METHODS Data were collected retrospectively on patients operated at our institution between 2004 and 2014. A Cox proportional hazards model was used to investigate the relationship between clinical and pathological parameters, NLR and PLR to overall survival (OS). Survival data were analyzed using the Kaplan-Meier method. RESULTS 217 patients were analyzed with a median overall survival (OS) of 17.5 months. Factors identified as being predictive of OS by univariate analysis included age, receipt of adjuvant therapy, margin positivity, pathologic angiolymphatic invasion, T-stage, and N-stage (P < 0.05). Factors identified as being independently predictive of OS by multivariate analysis included age and angiolymphatic invasion (P < 0.05). NLR and PLR were not predictive of OS. Survival analysis demonstrated no difference in OS in patients who had high or low NLR or PLR. DISCUSSION Pretherapy NLR and PLR do not predict survival in patients who underwent pancreatectomy for PDAC at our institution.
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Abstract
Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.
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Affiliation(s)
- Francesca Aroldi
- UO Oncologia, Poliambulanza Foundation, Via Bissolati 57, 25124 Brescia, Italy
| | - Alberto Zaniboni
- UO Oncologia, Poliambulanza Foundation, Via Bissolati 57, 25124 Brescia, Italy
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21
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Mojic M, Takeda K, Hayakawa Y. The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion. Int J Mol Sci 2017; 19:E89. [PMID: 29283429 PMCID: PMC5796039 DOI: 10.3390/ijms19010089] [Citation(s) in RCA: 240] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 12/26/2017] [Accepted: 12/26/2017] [Indexed: 02/07/2023] Open
Abstract
Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark "tumor-promoting" side effect of IFN-γ. In this review, we will summarize this multi-functional role of IFN-γ in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-γ is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment.
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Affiliation(s)
- Marija Mojic
- Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
| | - Kazuyoshi Takeda
- Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
- Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
| | - Yoshihiro Hayakawa
- Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
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22
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Tang WG, Hu B, Sun HX, Sun QM, Sun C, Fu PY, Yang ZF, Zhang X, Zhou CH, Fan J, Ren N, Xu Y. Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis. Oncotarget 2017; 8:102006-102019. [PMID: 29254221 PMCID: PMC5731931 DOI: 10.18632/oncotarget.22039] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 08/28/2017] [Indexed: 12/24/2022] Open
Abstract
The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-γ-induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo. Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC.
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Affiliation(s)
- Wei-Guo Tang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China.,Department of Surgery, Minhang Branch of Zhongshan Hospital, Fudan University, Shanghai 201199, P. R. China.,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, P. R. China
| | - Bo Hu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Hai-Xiang Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Qi-Man Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Chao Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Pei-Yao Fu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Zhang-Fu Yang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Xin Zhang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Chen-Hao Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
| | - Ning Ren
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China.,Department of Surgery, Minhang Branch of Zhongshan Hospital, Fudan University, Shanghai 201199, P. R. China.,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, P. R. China
| | - Yang Xu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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23
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Solinas C, Pusole G, Demurtas L, Puzzoni M, Mascia R, Morgan G, Giampieri R, Scartozzi M. Tumor infiltrating lymphocytes in gastrointestinal tumors: Controversies and future clinical implications. Crit Rev Oncol Hematol 2016; 110:106-116. [PMID: 28109400 DOI: 10.1016/j.critrevonc.2016.11.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 11/06/2016] [Accepted: 11/23/2016] [Indexed: 02/08/2023] Open
Abstract
Chronic inflammation following infections, autoimmune diseases or exposure to environmental irritants plays a crucial role in tumor development and influences the host immune response to neoplastic cells. The presence of an anti-tumor immune infiltrate is often associated with better outcomes in gastro-intestinal primary cancers, particularly in those with high microsatellite instability (MSI-H). Immunotherapeutic drugs inhibiting the PD-1 and PD-L1 pathway showed promising results in the treatment of these patients in the metastatic setting. The aim of this review is to resume the role tumor infiltrating lymphocytes (TILs) play in gastrointestinal tumors, underlining their potential value as a prognostic and predictive biomarker. TILs assessment could identify subsets of patients with high extent of TILs and better prognosis, that could be spared from adjuvant systemic treatments. Immune infiltration parameters might be additional predictors of a greater benefit from the immunotherapy with the immune checkpoint blockade.
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Affiliation(s)
- Cinzia Solinas
- Molecular Immunology Unit, Institut Jules Bordet and Université Libre de Bruxelles, Boulevard de Waterloo, 127 1000 Brussels, Belgium.
| | - Grazia Pusole
- Medical Oncology, University of Cagliari, Policlinico Universitario ss 554 bivio Sestu km 4.5, Monserrato, CA, Italy.
| | - Laura Demurtas
- Medical Oncology, University of Cagliari, Policlinico Universitario ss 554 bivio Sestu km 4.5, Monserrato, CA, Italy.
| | - Marco Puzzoni
- Medical Oncology, University of Cagliari, Policlinico Universitario ss 554 bivio Sestu km 4.5, Monserrato, CA, Italy.
| | - Roberta Mascia
- Medical Oncology, University of Cagliari, Policlinico Universitario ss 554 bivio Sestu km 4.5, Monserrato, CA, Italy.
| | | | | | - Mario Scartozzi
- Medical Oncology, University of Cagliari, Policlinico Universitario ss 554 bivio Sestu km 4.5, Monserrato, CA, Italy.
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24
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Gimeno Brias S, Stack G, Stacey MA, Redwood AJ, Humphreys IR. The Role of IL-22 in Viral Infections: Paradigms and Paradoxes. Front Immunol 2016; 7:211. [PMID: 27303405 PMCID: PMC4885595 DOI: 10.3389/fimmu.2016.00211] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022] Open
Abstract
Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. Hematopoietic cells express IL-22, and this cytokine signals through the heterodimeric IL-22 receptor expressed by non-hematopoietic cells. A growing body of evidence points toward a role for IL-22 in a diverse array of biological functions ranging from cellular proliferation, tissue protection and regeneration, and inflammation. In recent years, the role that IL-22 plays in antiviral immune responses has been examined in a number of infection models. Herein, we assess our current understanding of how IL-22 determines the outcome of viral infections and define common mechanisms that are evident from, sometimes paradoxical, findings derived from these studies. Finally, we discuss the potential therapeutic utility of IL-22 manipulation in the treatment and prevention of viral infections and associated pathologies.
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Affiliation(s)
- Silvia Gimeno Brias
- Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - Gabrielle Stack
- Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - Maria A Stacey
- Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - Alec J Redwood
- The Institute for Immunology and Infectious Diseases, Murdoch University , Murdoch, WA , Australia
| | - Ian R Humphreys
- Institute of Infection and Immunity, Cardiff University, Cardiff, UK; Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
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25
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Kajihara M, Takakura K, Kanai T, Ito Z, Matsumoto Y, Shimodaira S, Okamoto M, Ohkusa T, Koido S. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer. World J Gastroenterol 2016; 22:4446-58. [PMID: 27182156 PMCID: PMC4858628 DOI: 10.3748/wjg.v22.i18.4446] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/01/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.
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26
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Jimenez-Luna C, Prados J, Ortiz R, Melguizo C, Torres C, Caba O. Current Status of Immunotherapy Treatments for Pancreatic Cancer. J Clin Gastroenterol 2016; 50:836-848. [PMID: 27505403 DOI: 10.1097/mcg.0000000000000623] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer (PC) is a lethal disease representing the seventh most frequent cause of death from cancer worldwide. Resistance of pancreatic tumors to current treatments leads to disappointing survival rates, and more specific and effective therapies are urgently needed. In recent years, immunotherapy has been proposed as a promising approach to the treatment of PC, and encouraging results have been published by various preclinical and clinical studies. This review provides an overview of the latest developments in the immunotherapeutic treatment of PC and summarizes the most recent and important clinical trials.
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Affiliation(s)
- Cristina Jimenez-Luna
- *Institute of Biopathology and Regenerative Medicine (IBIMER) ‡Department of Biochemistry and Molecular Biology I, Universidad de Granada, Granada †Department of Health Sciences, Universidad de Jaen, Jaen, Spain
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