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Liu J, Zhang T, Gao Y, Ji D, Chen L. Causal role of immune cells in primary liver cancer: a mendelian randomization study. BMC Cancer 2025; 25:928. [PMID: 40410708 PMCID: PMC12100895 DOI: 10.1186/s12885-025-14327-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/13/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Primary liver cancer is one of the most common fatal malignancies worldwide. Observational studies have shown that immune cells are closely linked to primary liver cancer, however, due to issues like reverse causality and confounding variables, the causal direction and extent of this association remain unclear. Thus, this study aimed to explore the potential causal association between immune cells and primary liver cancer, encompassing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS A two-sample mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWAS) of the 731 immune traits and primary liver cancer. The primary liver cancer dataset consisted of a total of 456,348 subjects, with 123 cases of HCC and 456,225 controls, as well as 104 cases of ICC and 456,244 controls, all of European ancestry. The primary method for assessing causality was inverse variance weighting (IVW), with sensitivity analysis utilized for testing heterogeneity and pleiotropy. RESULTS Two immunophenotypes were significantly associated with HCC risk: CD3 on CD45RA + CD4+ (OR [95% CI]: 1.334 [1.077 to 1.651], p = 0.008), CD80 on monocyte (OR [95% CI]: 0.578 [0.397 to 0.844], p = 0.004). Additionally, six immunophenotypes were identified to be significantly associated with the risk of ICC: SSC-A on NK (OR [95% CI]: 1.685 [1.166 to 2.436], p = 0.006); CD3 on CD28- CD8br: (OR [95% CI]: 1.826 [1.206 to 2.766], p = 0.004); CD45RA on naive CD4+: (OR [95% CI]: 1.391 [1.119 to 1.729], p = 0.003); Resting Treg %CD4: (OR [95% CI]: 1.290 [1.069 to 1.558], p = 0.008); HLA DR on HSC: (OR [95% CI]: 0.539 [0.343 to 0.846], p = 0.007); Plasmacytoid DC %DC: (OR [95% CI]: 0.610 [0.462 to 0.806], p < 0.001). And sensitivity analyses confirmed the robustness of the main findings. CONCLUSIONS MR analysis has revealed the causal relationship between immune cells and primary liver cancer through genetic methods. These findings could assist in clinical decision-making and provide new directions for the treatment and research of primary liver cancer.
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Affiliation(s)
- Jia Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Tongyuan Zhang
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Yang Gao
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Dong Ji
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Lijian Chen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
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Han SH, Ju MH, Pak MG. Prognostic and therapeutic potential of CXCR6 expression on CD8 + T cells in gastric cancer: a retrospective cohort study. BMC Gastroenterol 2025; 25:139. [PMID: 40050760 PMCID: PMC11884069 DOI: 10.1186/s12876-025-03735-z] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 02/26/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a pressing global health concern, with prognosis intricately linked to the tumour stage and tumour microenvironment, especially, the presence of immune cells. Notably, CD8 + T cells play a pivotal role in the anti-tumour immune response, prompting investigations into their correlation with GC survival. This study aimed to investigate the intricate interplay between CD8 + T cells, particularly within the context of CXCR6, and survival outcomes in patients with GC. METHODS Utilising datasets from The Cancer Genome Atlas, Gene Expression Omnibus, and Tumor Immune Dysfunction and Exclusion, the study employed xCell and Weighted Gene Co-expression Network Analysis to assess CD8 + T cell infiltration and identify key gene clusters. The prognostic significance of CXCR6 was evaluated via immunohistochemical staining of a GC tissue microarray. RESULTS High CD8 + T cell infiltration correlated with improved survival in patients with GC. CXCR6 was identified as a prognostic gene and its expression was predominantly observed in CD8 + T cells. CXCR6 expression positively correlated with improved overall and disease-free survival. Furthermore, CXCR6 expression was associated with an immunoreactive microenvironment. CONCLUSION This study established that high CD8 + T-cell infiltration is related to CXCR6 expression, making it a key factor in predicting a favorable GC prognosis. The role of CXCR6 in shaping the tumour microenvironment and its potential utility in immunotherapy response prediction highlights its significance in GC management.
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Affiliation(s)
- Song-Hee Han
- Department of Pathology, Dong-A University College of Medicine, Busan, 49201, Republic of Korea.
| | - Mi Ha Ju
- Department of Pathology, Dong-A University College of Medicine, Busan, 49201, Republic of Korea
| | - Min Gyoung Pak
- Department of Pathology, Dong-A University College of Medicine, Busan, 49201, Republic of Korea
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Lee JY, Kim JW. Recent 5‑year trends in biliary tract cancer survival rates: An analytical big data survey. MEDICINE INTERNATIONAL 2025; 5:15. [PMID: 39882400 PMCID: PMC11775868 DOI: 10.3892/mi.2025.214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 12/18/2024] [Indexed: 01/31/2025]
Abstract
Biliary tract cancer (BTC), also known as cholangiocarcinoma, is a relatively rare type of cancer with a poor prognosis. Despite the combination of chemotherapy and advances in targeted therapy, which have potentially improved the prognosis of patients with BTC, research on outcomes remains inadequate. The present study thus analyzed the survival trends of patients with BTC. The present study used anonymized data from a public national database and focused on 13,600 individuals diagnosed with BTC between 2015 and 2020. The overall and 1-year mortality rates were analyzed according to cancer anatomic sites, along with the impact of comorbidities, such as diabetes and hepatitis on these rates. A total of 13,600 patients were included in the analysis; 26.31% of the patients had intrahepatic BTC, 27.46% had extrahepatic BTC and 46.24% had gallbladder (GB) cancer. For all BTC types, the 1-year survival hazard ratio (HR) in 2018 was 0.992 compared with that in 2015, and 0.986 in 2019. Compared with intrahepatic BTC, the 1-year survival rate was 0.349 for GB cancer and 0.641 for extrahepatic BTC. Patients with diabetes had an HR of 1.318 compared with those without diabetes. For patients with BTC previously diagnosed with GB stones, the survival HR was 0.902, compared to those without GB stones. On the whole, the analysis of national healthcare big data indicated an improvement in the overall prognosis of patients with BTC from 2018. Moreover, these data highlight that the prognosis of patients with BTC is influenced by the anatomical location of the cancer, and that co-existing medical conditions in patients affect the survival rate.
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Affiliation(s)
- Ji Yoon Lee
- Department of Biostatistics, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Ju Won Kim
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Fu M, Zhou H, Yang J, Cao D, Yuan Z. Infiltration of CD8 + cytotoxic T-cells and expression of PD-1 and PD-L1 in ovarian clear cell carcinoma. Sci Rep 2025; 15:4716. [PMID: 39922892 PMCID: PMC11807128 DOI: 10.1038/s41598-025-89270-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 02/04/2025] [Indexed: 02/10/2025] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is resistant to chemotherapy, with limited treatment options for advanced and recurrent disease. The prevalence of OCCC differs by region. Assessing the expression of programmed cell death ligand 1 (PD-L1), PD-1, and CD8+T cell infiltration in OCCC is crucial, as their correlation with patient survival may provide valuable prognostic insights. We collected data from 36 samples from 18 OCCC patients, including 18 pairs of tumors and adjacent nonneoplastic samples. The optimized multiplex immunofluorescence technique was used to stain paraffin sections for immune factors related to the immune microenvironment of OCCC and clinical prognosis. The expression of PDL1 and PD1 in the tumor cells and tumor stromal cells was not significantly correlated with prognosis. Professional quantitative pathological analysis software was used to count the CD8+ cytotoxic T-cells in tumor regions and adjacent nonneoplastic regions in postoperative specimens. There were more CD8+ cytotoxic T-cells in the adjacent nonneoplastic areas than in the tumor tissue samples (p < 0.001). Further analysis revealed that a difference in cell density between CD8+ non-tumor-infiltrating lymphocytes (NTILs) and CD8+ tumor-infiltrating lymphocytes (TILs) exceeding 70 cells/mm2 was associated with poorer progression-free survival (PFS) (p = 0.042). In adjacent nonneoplastic regions, worse PFS was significantly observed in patients with high CD8+ T-cell expression in both total and stromal cells than those with low expression (p = 0.012 vs p = 0.007). The presence of CD8+ T-cells had significant potential for predicting the prognosis of patients with OCCC, which lays a foundation for the development of biomarkers for immune checkpoint blockade treatment response in OCCC patients.
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Affiliation(s)
- Mengdi Fu
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
| | - Huimei Zhou
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Jiaxin Yang
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Dongyan Cao
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China.
| | - Zhen Yuan
- Department of Obstetrics and Gynecology, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, China
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Porro N, Spínola-Lasso E, Pastore M, Caligiuri A, di Tommaso L, Marra F, Gentilini A. New Relevant Evidence in Cholangiocarcinoma Biology and Characterization. Cancers (Basel) 2024; 16:4239. [PMID: 39766138 PMCID: PMC11674836 DOI: 10.3390/cancers16244239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Among solid tumors, cholangiocarcinoma (CCA) emerges as one of the most difficult to eradicate. The silent and asymptomatic nature of this tumor, particularly in its early stages, as well as the high heterogeneity at genomic, epigenetic, and molecular levels delay the diagnosis, significantly compromising the efficacy of current therapeutic options and thus contributing to a dismal prognosis. Extensive research has been conducted on the molecular pathobiology of CCA, and recent advances have been made in the classification and characterization of new molecular targets. Both targeted therapy and immunotherapy have emerged as effective and safe strategies for various types of cancers, demonstrating potential benefits in advanced CCA. Furthermore, the deeper comprehension of the cellular and molecular components in the tumor microenvironment (TME) has opened up possibilities for new innovative treatment methods. This review discusses recent evidence in the characterization and molecular biology of CCA, highlighting novel possible druggable targets.
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Affiliation(s)
- Nunzia Porro
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
| | - Elena Spínola-Lasso
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
| | - Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
| | - Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
| | - Luca di Tommaso
- Department of Biomedical Sciences, Humanitas University, 20089 Milan, Italy;
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
| | - Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (N.P.); (E.S.-L.); (M.P.); (A.C.); (F.M.)
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Liu S, Weng J, Cao M, Zhou Q, Xu M, Xu W, Hu Z, Xu M, Dong Q, Sheng X, Zhou C, Ren N. FGFR2 fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma. Oncologist 2024; 29:e1734-e1747. [PMID: 38986528 PMCID: PMC11630758 DOI: 10.1093/oncolo/oyae170] [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] [Received: 03/02/2024] [Accepted: 06/10/2024] [Indexed: 07/12/2024] Open
Abstract
Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.
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Affiliation(s)
- Shaoqing Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Jialei Weng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Manqing Cao
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China
| | - Qiang Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Min Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Wenxin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Zhiqiu Hu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China
| | - Minghao Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Qiongzhu Dong
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China
| | - Xia Sheng
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China
- Department of Pathology, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China
| | - Chenhao Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
| | - Ning Ren
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai, 201199, People’s Republic of China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of China
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Toshida K, Itoh S, Iseda N, Izumi T, Bekki Y, Yoshiya S, Toshima T, Iwasaki T, Oda Y, Yoshizumi T. The Association of Transferrin Receptor with Prognosis and Biologic Role in Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2024; 31:8627-8637. [PMID: 39179864 DOI: 10.1245/s10434-024-16065-3] [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: 06/03/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND Ferroptosis is a cell death caused by iron-dependent accumulation of lipid peroxidation. Transferrin receptor (TFR) is a ferroptosis-related protein responsible for iron transport. The detailed biologic role of TFR in intrahepatic cholangiocarcinoma (ICC) is not fully elucidated. METHODS The study enrolled 92 ICC patients who had undergone hepatic resection. Immunohistochemistry (IHC) assays were performed for TFR protein expression. The regulation of malignant activity and the effect on sensitivity to the ferroptosis-inducer artesunate by TFR were investigated in vitro. RESULTS Using IHC staining, 23 patients were categorized as TFR-positive. The TFR-positive group had a significantly larger tumor size and more microscopic vascular invasion. In the multivariate analysis, TFR positivity was an independent poor prognostic factor. In vitro TFR-knockdown (KD) significantly decreased the intracellular iron levels and the cell proliferation, migration, and invasion rates. Artesunate treatment significantly decreased cell viability, whereas cisplatin promoted ferroptosis. When iron transport into cells was inhibited by TFR-KD, ferroptosis was significantly suppressed. Expression of PD-L1 was induced by cisplatin, with a further increase observed when artesunate and cisplatin were used in combination. CONCLUSIONS Transferrin receptor is a poor prognostic factor for ICC and contributes to sensitivity to ferroptosis.
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Affiliation(s)
- Katsuya Toshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Norifumi Iseda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takuma Izumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Bekki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Iwasaki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Wang ZR, Zhang CZ, Ding Z, Li YZ, Yin JH, Li N. Establishing prognostic models for intrahepatic cholangiocarcinoma based on immune cells. World J Gastrointest Oncol 2024; 16:4092-4103. [DOI: 10.4251/wjgo.v16.i10.4092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/26/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a malignant liver tumor that is challenging to treat and manage and current prognostic models for the disease are inefficient or ineffective. Tumor-associated immune cells are critical for tumor development and progression. The main goal of this study was to establish models based on tumor-associated immune cells for predicting the overall survival of patients undergoing surgery for ICC.
AIM To establish 1-year and 3-year prognostic models for ICC after surgical resection.
METHODS Immunohistochemical staining was performed for CD4, CD8, CD20, pan-cytokeratin (CK), and CD68 in tumors and paired adjacent tissues from 141 patients with ICC who underwent curative surgery. Selection of variables was based on regression diagnostic procedures and goodness-of-fit tests (PH assumption). Clinical parameters and pathological diagnoses, combined with the distribution of immune cells in tumors and paired adjacent tissues, were utilized to establish 1- and 3-year prognostic models.
RESULTS This is an important application of immune cells in the tumor microenvironment. CD4, CD8, CD20, and CK were included in the establishment of our prognostic model by stepwise selection, whereas CD68 was not significantly associated with the prognosis of ICC. By integrating clinical data associated with ICC, distinct prognostic models were derived for 1- and 3-year survival outcomes using variable selection. The 1-year prediction model yielded a C-index of 0.76 95% confidence interval (95%CI): 0.65-0.87 and the 3-year prediction model produced a C-index of 0.69 (95%CI: 0.65-0.73). Internal validation yielded a C-index of 0.761 (95%CI: 0.669-0.853) for the 1-year model and 0.693 (95%CI: 0.642-0.744) for the 3-year model.
CONCLUSION We developed Cox regression models for 1-year and 3-year survival predictions of patients with ICC who underwent resection, which has positive implications for establishing a more comprehensive prognostic model for ICC based on tumor immune microenvironment and immune cell changes in the future.
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Affiliation(s)
- Zhuo-Ran Wang
- Department of Hepatic Surgery I (Ward I) Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Navy Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Navy Medical University, Shanghai 200433, China
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai 200433, China
| | - Cun-Zhen Zhang
- Department of Hepatic Surgery I (Ward I) Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200433, China
| | - Zhan Ding
- Key Laboratory of Biological Defense, Ministry of Education, Navy Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Navy Medical University, Shanghai 200433, China
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai 200433, China
| | - Yi-Zhuo Li
- Department of Oncology, 905 Hospital of People’s Liberation Army Navy, Shanghai 200050, China
| | - Jian-Hua Yin
- Key Laboratory of Biological Defense, Ministry of Education, Navy Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Navy Medical University, Shanghai 200433, China
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai 200433, China
| | - Nan Li
- Department of Hepatic Surgery I (Ward I) Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai 200433, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Lozzi I, Arnold A, Barone M, Johnson JC, Sinn BV, Eschrich J, Gebert P, Wang R, Hu M, Feldbrügge L, Schirmeier A, Reutzel-Selke A, Malinka T, Krenzien F, Schöning W, Modest DP, Pratschke J, Sauer IM, Felsenstein M. Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma. Oncoimmunology 2024; 13:2406052. [PMID: 39359389 PMCID: PMC11445892 DOI: 10.1080/2162402x.2024.2406052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 08/06/2024] [Accepted: 09/14/2024] [Indexed: 10/04/2024] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation. Methods Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53). Results CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression. Conclusions These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.
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Affiliation(s)
- Isis Lozzi
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alexander Arnold
- Department of Pathology, CCM, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Matthias Barone
- Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
| | - Juliette Claire Johnson
- Translational Immunology, Berlin Institute of Health & Charité University Medicine, Berlin, Germany
| | - Bruno V Sinn
- Department of Pathology, CCM, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johannes Eschrich
- Department of Hepatology and Gastroenterology, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Pimrapat Gebert
- Institute of Biometry and Clinical Epidemiology, CCM, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ruonan Wang
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mengwen Hu
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Linda Feldbrügge
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Anja Schirmeier
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thomas Malinka
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Dominik P Modest
- Department of Hematology, Oncology, and Cancer Immunology, CCM, CVK, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
- DKFZ, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Matthäus Felsenstein
- Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Charité Clinician Scientist Program Charité - Universitätsmedizin Berlin and The Berlin Institute of Health at Charité (BIH), Berlin, Germany
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Li C, Dong Y, Zhang Y, Wu C. Clinical significance of lncRNA XIST expression in cholangiocarcinoma and its effect on cell migration and invasion. Clin Res Hepatol Gastroenterol 2024; 48:102398. [PMID: 38871250 DOI: 10.1016/j.clinre.2024.102398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Cholangiocarcinoma is a malignant tumor that occurs in the bile duct system, and the prognosis of patients is poor. Currently, research suggests that long non-coding RNAs (lncRNAs) in the treatment and prevention of cholangiocarcinoma. This study primarily focuses on the regulation and potential mechanism of the lncRNA XIST (XIST) in cholangiocarcinoma. METHODS The levels of XIST and miR-126-3p in cholangiocarcinoma tissues and cells were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell transfection status, including migration and invasion, was examined via the Transwell method. The relationship between XIST and miR-126-3p was observed by dual-luciferase gene reporter assay and verified by rescue assays. Additionally, the prognostic significance of XIST in cholangiocarcinoma was determined using Kaplan-Meier and multivariate Cox regression analyses. RESULTS XIST expression was increased in cholangiocarcinoma, while miR-126-3p was decreased, in both tissues and cells. The successful construction of silencing XIST was found to inhibit the count of cell migration and invasion. XIST directly targeted miR-126-3p to regulate the progression of cholangiocarcinoma. CONCLUSION XIST sponging miR-126-3p inhibited the progression of cholangiocarcinoma and improved the prognosis for patients. This finding provides new insights and opportunities for future studies on cholangiocarcinoma prognostic biomarkers.
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Affiliation(s)
- Chenxi Li
- Department of General Surgery, Wenling Hospital of Traditional Chinese Medicine, Wenling 317500, China
| | - Yifei Dong
- Department of Laboratory, The Eighth Hospital of Wuhan, Wuhan 430010, China
| | - Yichuan Zhang
- Minimally Invasive Endoscopy Center, Digestive Disease Center, The Affiliated Hospital of Panzhihua University, Panzhihua 617000, China.
| | - Caihong Wu
- Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha 421001, China; Anesthesia Medical Research Center of Central South University, Changsha 421001, China; Department of Clinical Nursing, The Second Xiangya Hospital of Central South University, Changsha 421001, China.
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11
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Hua S, Gu X, Jin H, Zhang X, Liu Q, Yang J. Tumor-infiltrating T lymphocytes: A promising immunotherapeutic target for preventing immune escape in cholangiocarcinoma. Biomed Pharmacother 2024; 177:117080. [PMID: 38972151 DOI: 10.1016/j.biopha.2024.117080] [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: 04/22/2024] [Revised: 06/22/2024] [Accepted: 06/29/2024] [Indexed: 07/09/2024] Open
Abstract
Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; collectively, they constitute a significant portion of the tumor microenvironment (TME) in CCA. By secreting cytokines and other chemicals, regulatory T cells (Tregs) decrease activated T cell responses, acting as immunosuppressors. Reduced CD8+ T cell activation results in stimulating programmed death-1 (PD-1), which undermines the immunological homeostasis of T lymphocytes. On the other hand, cancer cells are eliminated by activated cytotoxic T lymphocyte (CTL) through the perforin-granzyme or Fas-FasL pathways. Th1 and CTL immune cell infiltration into the malignant tumor is also facilitated by γδ T cells. A higher prognosis is typically implied by CD8+ T cell infiltration, and survival is inversely associated with Treg cell density. Immune checkpoint inhibitors, either singly or in combination, provide novel therapeutic strategies for CCA immunotherapy. Furthermore, it is anticipated that immunotherapeutic strategies-such as the identification of new immune targets, combination treatments involving several immune checkpoint inhibitors, and chimeric antigen receptor-T therapies (CAR-T)-will optimize the effectiveness of anti-CCA treatments while reducing adverse effects.
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Affiliation(s)
- Sijia Hua
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China.
| | - Xinyi Gu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China.
| | - Hangbin Jin
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaofeng Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research, Hangzhou, Zhejiang 310003, China.
| | - Qiang Liu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Jianfeng Yang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital. School of Medicine, Westlake University, Hangzhou, Zhejiang, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research, Hangzhou, Zhejiang 310003, China.
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Chick RC, Ruff SM, Pawlik TM. Factors associated with prognosis and staging of intrahepatic cholangiocarcinoma. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2024.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but aggressive primary liver cancer with a poor prognosis. A number of established clinical and pathologic factors correlate with prognosis, and this is reflected in the American Joint Committee on Cancer (AJCC) 8th Edition staging manual. Researchers have identified areas for improvement in staging and prognostication of ICC using more nuanced tools, including serum biomarkers, molecular profiling, immunophenotyping, and multimodal prognostic scoring systems. These data have led to proposals of novel staging systems that attempt to improve the correlation between stage and prognosis. More accurate staging tools may aid in treatment decisions that are tailored to each individual patient, to maximize therapy for individuals most likely to benefit and to avoid unnecessary toxicity and decision regret in those for whom aggressive treatment is unlikely to alter outcomes. Artificial intelligence and machine learning may help researchers develop new models that predict outcomes with more accuracy and precision.
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Chen F, Sheng J, Li X, Gao Z, Zhao S, Hu L, Chen M, Fei J, Song Z. Unveiling the promise of PD1/PD-L1: A new dawn in immunotherapy for cholangiocarcinoma. Biomed Pharmacother 2024; 175:116659. [PMID: 38692063 DOI: 10.1016/j.biopha.2024.116659] [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: 03/18/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024] Open
Abstract
Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.
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Affiliation(s)
- Fei Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jian Sheng
- Department of Research and Teaching, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaoping Li
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhaofeng Gao
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Siqi Zhao
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Lingyu Hu
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Minjie Chen
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Jianguo Fei
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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Shahin M, Patra S, Purkait S, Kar M, Das Majumdar SK, Mishra TS, Samal SC, Nayak HK. PD-L1 Expression in Colorectal Carcinoma Correlates with the Immune Microenvironment. J Gastrointest Cancer 2024; 55:940-949. [PMID: 38530597 DOI: 10.1007/s12029-024-01049-z] [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: 03/20/2024] [Indexed: 03/28/2024]
Abstract
INTRODUCTION/BACKGROUND Colorectal carcinoma (CRC) is a common malignancy, with its diverse clinical, pathological, and molecular features. The immune microenvironment of a tumor comprises of interplay between various cells and molecules, and has a significant role in deciding the tumor behavior and overall prognosis. PD-L1 (programmed cell death ligand-1) has been implicated in the regulation of the tumor immune microenvironment (TIME). There is limited data regarding the correlation of PD-L1 expression with immune cell profile in CRCs, especially in the Indian setting. The study aimed to assess the PD-L1 expression in CRC tumor cells and its association with TIME, mismatch repair (MMR), and various other clinicopathological parameters. METHODS This is a hospital-based, cross-sectional observational study. PD-L1 expression was assessed at the protein level by immunohistochemistry and mRNA level by qRT-PCR. Immune cell markers (CD4, CD8, CD20, FOXP3, and CD163) were interpreted using the ImageJ Fiji platform. RESULTS Of the 104 cases, 21% were PD-L1 positive and were more common in right-sided CRCs. PD-L1 positive cases showed significantly higher concentrations of all T-cell subsets (CD4+ , CD8+ , and FOXP3+), CD20+ B-cells, and CD163+ macrophages were noted. No statistical significance was seen between PD-L1 expression with clinical profile, pathological subtype, grade or stage, mismatch repair status (proficient vs deficient), and survival. CONCLUSIONS The present study showed a relatively lower frequency of PD-L1 in CRC from the Eastern Indian cohort. The immune cell concentration in the present study was calculated using image analysis-based objectivised methods. Significant correlation of PD-L1 expression in tumor cells with the tumor-infiltrating immune cells indicated its crucial role in the pathobiology of CRC especially by regulating the TIME. Considering the therapeutic implication of PD-L1 in various malignancies, it may be one of the crucial therapeutic targets in a proportion of cases.
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Affiliation(s)
- Mohammed Shahin
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Susama Patra
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India.
| | - Suvendu Purkait
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Madhabananda Kar
- Department of Surgical Oncology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Saroj Kumar Das Majumdar
- Department of Radiation Oncology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | | | - Subash Chandra Samal
- Department of Medical Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Hemanta Kumar Nayak
- Department of Medical Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
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Khosla D, Misra S, Chu PL, Guan P, Nada R, Gupta R, Kaewnarin K, Ko TK, Heng HL, Srinivasalu VK, Kapoor R, Singh D, Klanrit P, Sampattavanich S, Tan J, Kongpetch S, Jusakul A, Teh BT, Chan JY, Hong JH. Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches. Cancers (Basel) 2024; 16:801. [PMID: 38398194 PMCID: PMC10887007 DOI: 10.3390/cancers16040801] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/05/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.
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Affiliation(s)
- Divya Khosla
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shagun Misra
- Department of Radiotherapy and Oncology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Pek Lim Chu
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Peiyong Guan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rajesh Gupta
- Department of GI Surgery, HPB, and Liver Transplantation, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Khwanta Kaewnarin
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Tun Kiat Ko
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Hong Lee Heng
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Vijay Kumar Srinivasalu
- Department of Medical Oncology, Mazumdar Shaw Medical Center, NH Health City Campus, Bommasandra, Bangalore 560099, India
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deepika Singh
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Poramate Klanrit
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand
| | - Jing Tan
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Bin Tean Teh
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
| | - Jason Yongsheng Chan
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
- Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Division of Medical Oncology, National Cancer Center, Singapore 168583, Singapore
| | - Jing Han Hong
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
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Salih SS, Abdelaziz MS, Abdelhag IM, Mosad AS. Expression of programmed death-ligand 1, IRF1 and CD8 T lymphocyte infiltration in a primary subset of breast cancer patients in Sudan. J Taibah Univ Med Sci 2024; 19:99-105. [PMID: 37876597 PMCID: PMC10590852 DOI: 10.1016/j.jtumed.2023.08.006] [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: 03/22/2023] [Revised: 06/26/2023] [Accepted: 08/28/2023] [Indexed: 10/26/2023] Open
Abstract
Objectives This study aimed to investigate the protein expression of programmed death ligand 1 (PD-L1) in breast cancer (BC) tissues and link this data with estrogen status, the expression of interferon regulatory factor1 (IRF-1), and CD8+T lymphocyte infiltration by immunohistochemistry (IHC). We also attempted to identify the association between PD-L1 expression, the cell proliferation index marker (Ki67), and lymph node involvement. Methods One hundred and fifty formalin-fixed and paraffin-embedded (FFPE) blocks of breast tissue were acquired from Sudanese females via The National Public Health Laboratory. FFPE blocks were subjected to antigen/antibody detection by IHC with antibodies raised against PD-L1, IRF1, and CD8. These data were analyzed alongside data extracted from medical records relating to estrogen receptor (ER) status, Ki67 index, and lymph node (LN) status. Results IHC analysis revealed a significant association between PD-L1 and CD8 (p = 0.010). In addition, regression analysis indicated the ability of IRF1 to induce PD-L1 expression levels in IRF1-positive cases that were two-fold higher than IRF1-deficient cases (odds ratio [OR]: 2.441 p = 0.035). Analysis also suggested that PD-L1 exerts impact on cell proliferation, as reflected by the Ki67 index. An independent t test showed that higher Ki67 scores were more frequent among PD-L1-positive patients than in PD-L1-negative patients (t = 2.608 p = 0.014). There was an inverse association between PD-L1 and ER status; ER-positive tumors exhibited negative PD-L1 expression and vice versa (p = 0.04). Furthermore, we investigated the prognostic value of PD-L1 by evaluating the association between PD-L1 and LNs dispersed variably with tumor cells; there was no statistically significant relationship between these factors (p > 0.05). Conclusion The expression of PD-L1 and IRF-1, along with the infiltration of CD8, represents a potent panel of biomarkers with which to identify BC patients with the highest probabilities of achieving an excellent response to immune therapy, particularly when taking ER status into account, as ER expression levels are known to be high when immune checkpoint blockers (ICBs) generate a poor response.
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Affiliation(s)
- Shahenaz S. Salih
- Department of Histopathology and Cytology, Sudan University of Science and Technology, Khartoum, Sudan
| | - Mohammed S. Abdelaziz
- Department of Histopathology and Cytology, Sudan University of Science and Technology, Khartoum, Sudan
| | - Ibtehal M. Abdelhag
- Department of Histopathology & Cytology, Omdurman Islamic University, Khartoum, Sudan
| | - Altaf S. Mosad
- Department of Histopathology and Cytology, Sudan University of Science and Technology, Khartoum, Sudan
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Gawiński C, Mróz A, Roszkowska-Purska K, Sosnowska I, Derezińska-Wołek E, Michalski W, Wyrwicz L. A Prospective Study on the Roles of the Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR) in Patients with Locally Advanced Rectal Cancer. Biomedicines 2023; 11:3048. [PMID: 38002048 PMCID: PMC10669751 DOI: 10.3390/biomedicines11113048] [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: 10/26/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Rectal cancer constitutes over one-third of all colorectal cancers (CRCs) and is one of the leading causes of cancer-related deaths in developed countries. In order to identify high-risk patients and better adjust therapies, new markers are needed. Systemic inflammatory response (SIR) markers such as LMR, NLR, and PLR have proven to be highly prognostic in many malignancies, including CRC; however, their roles in locally advanced rectal cancer (LARC) are conflicting and lack proper validation. Sixty well-selected patients with LARC treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between August 2017 and December 2020 were prospectively enrolled in this study. The reproducibility of the pre-treatment levels of the SIR markers, their correlations with clinicopathological characteristics, and their prognostic value were evaluated. There was a significant positive correlation between LMR and cancer-related inflammatory infiltrate (r = 0.38, p = 0.044) and PD-L1 expression in tumor cells, lymphocytes, and macrophages (combined positive score (CPS)) (r = 0.45, p = 0.016). The PLR level was correlated with nodal involvement (p = 0.033). The SIR markers proved to be only moderately reproducible and had no significant prognostic value. In conclusion, the LMR was associated with local cancer-related inflammation and PD-L1 expression in tumor microenvironments. The validity of SIR indices as biomarkers in LARC requires further investigation.
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Affiliation(s)
- Cieszymierz Gawiński
- Department of Oncology and Radiotherapy, M. Skłodowska-Curie National Research Institute of Oncology, ul. Wawelska 15, 02-034 Warsaw, Poland;
| | - Andrzej Mróz
- Department of Pathology, M. Skłodowska-Curie National Research Institute of Oncology, ul. Roentgena 5, 02-781 Warsaw, Poland; (A.M.); (I.S.); (E.D.-W.)
| | - Katarzyna Roszkowska-Purska
- Department of Pathology, M. Skłodowska-Curie National Research Institute of Oncology, ul. Wawelska 15, 02-034 Warsaw, Poland;
| | - Iwona Sosnowska
- Department of Pathology, M. Skłodowska-Curie National Research Institute of Oncology, ul. Roentgena 5, 02-781 Warsaw, Poland; (A.M.); (I.S.); (E.D.-W.)
| | - Edyta Derezińska-Wołek
- Department of Pathology, M. Skłodowska-Curie National Research Institute of Oncology, ul. Roentgena 5, 02-781 Warsaw, Poland; (A.M.); (I.S.); (E.D.-W.)
| | - Wojciech Michalski
- Department of Computation Oncology, M. Skłodowska-Curie National Research Institute of Oncology, ul. Roentgena 5, 02-781 Warsaw, Poland;
| | - Lucjan Wyrwicz
- Department of Oncology and Radiotherapy, M. Skłodowska-Curie National Research Institute of Oncology, ul. Wawelska 15, 02-034 Warsaw, Poland;
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18
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Zhang X, Li R, Wang G. PDL1-Based Nomogram May Be of Potential Clinical Utility for Predicting Survival Outcome in Stage III Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:731-746. [PMID: 37905205 PMCID: PMC10613449 DOI: 10.2147/bctt.s435980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/19/2023] [Indexed: 11/02/2023]
Abstract
Purpose Programmed cell death ligand 1 (PDL1) has the predictive and prognostic value in a great deal of cancers. This study aims to explore the expression of PDL1 in stage III breast cancer (BC) and its correlation with clinical outcome. Methods The protein expression of PDL1 in tumor tissues was determined by immunohistochemistry (IHC). The correlations between PDL1 and clinicopathological variables were performed by χ²-tests or Fisher's exact tests. The Cox proportional hazards model was used for univariate and multivariate analysis of the potential prognostic factors. Survival curves were estimated based on Kaplan-Meier analyses, and Log Rank test was used to contrast factors influencing the survival outcome. Results On the basis of the semiquantitative scoring method for PDL1 expression, the patients were divided into low PDL1 expression group (109 cases) and high PDL1 expression group (107 cases). PDL1 expression was correlated with positive lymph nodes, positive axillary lymph nodes, postoperative radiotherapy, and CK5/6 expression (P < 0.05). The PDL1 expression in tumor tissues was discovered to be a potential prognostic risk factor with the disease-free survival (DFS) and overall survival (OS) for stage III BC. Moreover, patients with high PDL1 expression showed longer lifetime (DFS and OS) compared to those with low PDL1 expression in total patient population (P < 0.05). Moreover, the nomogram showed that the prediction line is in good agreement with the reference line for postoperative 1-, 3-, and 5-year lifetime. The DCA curve showed that the 3- and 5-year lifetime by nomogram had so much better divination of the clinical application than only by PDL1. Conclusion PDL1 is a latent prognostic factor in stage III BC and is closely related to some clinicopathological features. PDL1 expression in tumor tissues is significantly associated with better lifetime rate in stage III BC.
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Affiliation(s)
- Xi Zhang
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China
| | - Ruzhe Li
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China
| | - Guonian Wang
- Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China
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Frega G, Cossio FP, Banales JM, Cardinale V, Macias RIR, Braconi C, Lamarca A. Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis. Cells 2023; 12:2098. [PMID: 37626908 PMCID: PMC10453268 DOI: 10.3390/cells12162098] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. METHODS Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. RESULTS A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs-15 studies), perihilar-distal CCAs (p/dCCAs-7 studies), and gallbladder cancer (GBC-5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. CONCLUSION From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.
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Affiliation(s)
- Giorgio Frega
- Osteoncology, Soft Tissue and Bone Sarcomas, Innovative Therapy Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Fernando P. Cossio
- Department of Organic Chemistry I, Center of Innovation in Advanced Chemistry (ORFEO-CINQA), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Donostia International Physics Center (DIPC), 48940 Donostia-San Sebastian, Spain;
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, 48940 San Sebastian, Spain;
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31009 Pamplona, Spain
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00185 Rome, Italy;
| | - Rocio I. R. Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain;
- Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, 37007 Salamanca, Spain
| | - Chiara Braconi
- School of Cancer Sciences, University of Glasgow, Glasgow G12 8QQ, UK;
- Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
| | - Angela Lamarca
- Department of Oncology—OncoHealth Institute, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
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Chen X, Dong L, Chen L, Wang Y, Du J, Ma L, Yan X, Huang J, Liao M, Chen X, Liu D, Li J, Zhang B, Teng W, Yuan K, Sun D, Gao Q, Zeng Y. Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies. Hepatobiliary Surg Nutr 2023; 12:478-494. [PMID: 37601000 PMCID: PMC10432305 DOI: 10.21037/hbsn-21-424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/23/2022] [Indexed: 08/22/2023]
Abstract
Background Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery. Methods An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort. Results The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment. Conclusions The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.
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Affiliation(s)
- Xing Chen
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Liangqing Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lu Chen
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Yuan Wang
- The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
- Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China
| | - Jinpeng Du
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Lijie Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaokai Yan
- Department of Oncology, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiwei Huang
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Mingheng Liao
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Xiangzheng Chen
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Dongming Liu
- Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Jin Li
- Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China
| | - Bo Zhang
- The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Wen Teng
- The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Kefei Yuan
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Deqiang Sun
- The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
- Department of Research and Development, Jiangsu Gaomei Genomics, Nanjing, China
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yong Zeng
- Department of Liver Surgery & Liver Transplantation, Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
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Lu X, Green BL, Xie C, Liu C, Chen X. Preclinical and clinical studies of immunotherapy for the treatment of cholangiocarcinoma. JHEP Rep 2023; 5:100723. [PMID: 37229173 PMCID: PMC10205436 DOI: 10.1016/j.jhepr.2023.100723] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 05/27/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a rare primary liver cancer associated with high mortality and few systemic treatment options. The behaviour of the immune system has come into focus as a potential treatment modality for many cancer types, but immunotherapy has yet to dramatically alter the treatment paradigm for CCA as it has for other diseases. Herein, we review recent studies describing the relevance of the tumour immune microenvironment (TIME) in CCA. Various non-parenchymal cell types are critically important in controlling CCA progression, prognosis, and response to systemic therapy. Knowledge of the behaviour of these leukocytes could help generate hypotheses to guide the development of potential immune-directed therapies. Recently, an immunotherapy-containing combination was approved for the treatment of advanced-stage CCA. However, despite level 1 evidence demonstrating the improved efficacy of this therapy, survival remained suboptimal. In the current manuscript, we provide a comprehensive review of the TIME in CCA, preclinical studies of immunotherapies against CCA, as well as ongoing clinical trials applying immunotherapies for the treatment of CCA. Particular emphasis is placed on microsatellite unstable tumours, a rare CCA subtype that demonstrates heightened sensitivity to approved immune checkpoint inhibitors. We also discuss the challenges involved in applying immunotherapies to the treatment of CCA and the importance of understanding the TIME.
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Affiliation(s)
- Xinjun Lu
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Benjamin L. Green
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Changqing Xie
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Chao Liu
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Chen
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
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22
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Wu T, Pu C, Wu X, Wang Q, Zhang K. Chemo-Free Treatment Using Anti-PD-1 Antibodies with Lenvatinib in Unresectable Gallbladder Cancer: PD-L1 May Be a Potential Biomarker for a Better Outcome. Diagnostics (Basel) 2023; 13:diagnostics13111833. [PMID: 37296684 DOI: 10.3390/diagnostics13111833] [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: 04/23/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Recently, anti-PD-1 antibodies plus lenvatinib has been administered in a series of solid tumors. Yet, the efficacy of chemo-free treatment of this combined therapy has seldom been reported in gallbladder cancer (GBC). The aim of our study was to initially evaluate the efficacy of the chemo-free treatment in unresectable GBCs. METHODS We retrospectively collected the clinical data of unresectable GBCs treated using chemo-free anti-PD-1 antibodies plus lenvatinib in our hospital from March 2019 to August 2022. The clinical responses were assessed, and PD-1 expression was evaluated. RESULTS Our study enrolled 52 patients, with the median progression-free survival being 7.0 months and the median overall survival being 12.0 months. The objective response rate was 46.2% and the disease control rate was 65.4%. The expression of PD-L1 in patients with objective response was significantly higher than those with progression of disease. CONCLUSIONS For patients with unresectable GBC, when not eligible for systemic chemotherapy, chemo-free treatment using anti-PD-1 antibodies with lenvatinib may become a safe and rational choice. The expression of PD-L1 in tumor tissues may be correlated to the objective response, and thus is expected to be a predictor of efficacy, and further clinical studies are certainly needed.
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Affiliation(s)
- Tiantian Wu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Beijing 102206, China
| | - Changsheng Pu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Beijing 102206, China
| | - Xianjia Wu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Beijing 102206, China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Beijing 102206, China
| | - Keming Zhang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Beijing 102206, China
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23
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Mocan LP, Craciun R, Grapa C, Melincovici CS, Rusu I, Al Hajjar N, Sparchez Z, Leucuta D, Ilies M, Sparchez M, Mocan T, Mihu CM. PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for patients with intrahepatic cholangiocarcinoma. Cancer Immunol Immunother 2023; 72:1003-1014. [PMID: 36251029 PMCID: PMC10991168 DOI: 10.1007/s00262-022-03309-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022]
Abstract
Cholangiocarcinoma, the second most common liver malignancy, after hepatocarcinoma is highly aggressive and usually diagnosed in advanced cases. In the era of personalized medicine, targeted therapy protocols are limited for cholangiocarcinoma and the only potential curative treatment, surgical resection, is seldom applicable.This retrospective study included all cases with pathology-confirmed intrahepatic cholangiocarcinoma admitted in a tertiary healthcare facility during a 10-year timeframe. Clinical information, laboratory values, imaging studies, and survival data were retrieved, and PD-L1 immunostaining was performed on representative pathology slides, for each case. From the total of 136 included cases (49 surgical resections and 87 liver biopsies), 38.97% showed PD-L1 positivity on tumoral cells, 34.8% on tumor infiltrating immune cells, 10.11% on epithelial cells within the peritumoral area and 15.95% on immune cells from the peritumoral area. Overall survival was significantly higher in the first two scenarios. However, after adjusting for age, tumor number, tumor size, and tumor differentiation in a multivariate analysis, only PD-L1 positivity on tumor infiltrating immune cells remained a favorable prognostic for survival. High immune cell counts also correlated with increased overall survival.Our study demonstrated that PD-1/PD-L1 checkpoint pathway in the microenvironment of intrahepatic cholangiocarcinoma bears prognostic significance. PD-L1 expression on immune cells, in both resection and biopsy specimens, might be a strong independent predictor for a favorable outcome.
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Affiliation(s)
- Lavinia Patricia Mocan
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Rares Craciun
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristiana Grapa
- Department of Physiology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Carmen Stanca Melincovici
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Rusu
- 3rd Pathology Department, Institute for Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Surgical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Zeno Sparchez
- 3rd Medical Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Daniel Leucuta
- Department of Medical Informatics and Biostatistics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Maria Ilies
- Department of Proteomics and Metabolomics, MedFUTURE Research Center for Advanced Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihaela Sparchez
- 2nd Pediatrics Department, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Tudor Mocan
- Department of Gastroenterology, "Octavian Fodor" Institute for Gastroenterology and Hepatology, Cluj-Napoca, Romania.
| | - Carmen Mihaela Mihu
- Department of Histology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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24
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Zhao LM, Shi AD, Yang Y, Liu ZL, Hu XQ, Shu LZ, Tang YC, Zhang ZL. Advances in molecular and cell therapy for immunotherapy of cholangiocarcinoma. Front Oncol 2023; 13:1140103. [PMID: 37064120 PMCID: PMC10090456 DOI: 10.3389/fonc.2023.1140103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly malignant tumor of the hepatobiliary system that has failed to respond to many traditional therapies to a certain extent, including surgery, chemotherapy and radiotherapy. In recent years, the new therapeutic schemes based on immunology have fundamentally changed the systemic treatment of various malignant tumors to a certain extent. In view of the immunogenicity of CCA, during the occurrence and development of CCA, some immunosuppressive substances are released from cells and immunosuppressive microenvironment is formed to promote the escape immune response of its own cells, thus enhancing the malignancy of the tumor and reducing the sensitivity of the tumor to drugs. Some immunotherapy regimens for cholangiocarcinoma have produced good clinical effects. Immunotherapy has more precise characteristics and less adverse reactions compared with traditional treatment approaches. However, due to the unique immune characteristics of CCA, some patients with CCA may not benefit in the long term or not benefit at all after current immunotherapy. At present, the immunotherapy of CCA that have been clinically studied mainly include molecular therapy and cell therapy. In this article, we generalized and summarized the current status of immunotherapy strategies including molecular therapy and cell therapy in CCA in clinical studies, and we outlined our understanding of how to enhance the clinical application of these immunotherapy strategies.
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Affiliation(s)
- Li-ming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - An-da Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yan Yang
- Department of General Surgery, Shanxian Central Hospital, Heze, China
| | - Zeng-li Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- Department of General Surgery, Qilu Hospital (Qingdao), Shandong University, Jinan, China
| | - Xiao-Qiang Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Li-Zhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yong-chang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
| | - Zong-li Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- *Correspondence: Yong-chang Tang, ; Zong-li Zhang,
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25
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MACC1 as a Potential Target for the Treatment and Prevention of Breast Cancer. BIOLOGY 2023; 12:biology12030455. [PMID: 36979146 PMCID: PMC10045309 DOI: 10.3390/biology12030455] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Metastasis associated in colon cancer 1 (MACC1) is an oncogene first identified in colon cancer. MACC1 has been identified in more than 20 different types of solid cancers. It is a key prognostic biomarker in clinical practice and is involved in recurrence, metastasis, and survival in many types of human cancers. MACC1 is significantly associated with the primary tumor, lymph node metastasis, distant metastasis classification, and clinical staging in patients with breast cancer (BC), and MACC1 overexpression is associated with reduced recurrence-free survival (RFS) and worse overall survival (OS) in patients. In addition, MACC1 is involved in BC progression in multiple ways. MACC1 promotes the immune escape of BC cells by affecting the infiltration of immune cells in the tumor microenvironment. Since the FGD5AS1/miR-497/MACC1 axis inhibits the apoptotic pathway in radiation-resistant BC tissues and cell lines, the MACC1 gene may play an important role in BC resistance to radiation. Since MACC1 is involved in numerous biological processes inside and outside BC cells, it is a key player in the tumor microenvironment. Focusing on MACC1, this article briefly discusses its biological effects, emphasizes its molecular mechanisms and pathways of action, and describes its use in the treatment and prevention of breast cancer.
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Lu Y, Zhang Q, Wang J, Zhang L. Characteristics and postoperative dynamic changes in circulating CD4 + helper T lymphocytes in patients with breast cancer. Front Oncol 2023; 13:1118346. [PMID: 36925914 PMCID: PMC10011473 DOI: 10.3389/fonc.2023.1118346] [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: 12/07/2022] [Accepted: 02/17/2023] [Indexed: 03/08/2023] Open
Abstract
Introduction Circulating CD4+ helper T cell (Th) subsets provide potentially important information on disease progression in several cancers. In this study, we explored the characteristics and postoperative dynamic changes in circulating CD4+Th subsets in patients with breast cancer. Methods Circulating CD4+Th subsets, including CD4+ naive T cells (Tn), CD4+ central memory T cells (Tcm), CD4+ effector memory T cells (Tem), CD4+CD57+T, and CD4+PD-1+T, were detected with multiparameter flow cytometry. T-test and Wilcoxon rank-sum test were used to compare differences between groups for normally and non-normally distributed continuous variables, respectively. Postoperative dynamic changes in CD4+Th subsets were assessed using the paired-sample rank-sum test. Results Seventy-five patients with invasive breast cancer and fifty-three patients with benign breast tumors were enrolled. Compared with that in patients with benign tumors, the proportion of CD4+Tn in patients with breast cancer patients decreased, whereas the proportion and absolute number of CD4+CD57+T and CD4+PD-1+T increased. Moreover, the proportion of CD4+PD-1+T was correlated with the clinicopathology of breast cancer. After tumor resection, the proportion and absolute number of CD4+Tcm significantly decreased, while those of CD4+Tem significantly increased, compared with preoperative values. Tumor resection caused significant changes in the proportion and absolute number of CD4+CD57+T and CD4+PD-1+ T, both of which showed significant decreases. Discussion We found significant changes in circulating CD4+Th subsets in patients with breast cancer. Additionally, complete tumor resection can benefit the patient as it balances the patient's immunosuppression and immune stress and improves the immune exhaustion and immunosenescence states.
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Affiliation(s)
- Yan Lu
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Qiaohong Zhang
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Jiang Wang
- Department of Breast Surgery, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Longyi Zhang
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
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Sarantis P, Trifylli EM, Koustas E, Papavassiliou KA, Karamouzis MV, Papavassiliou AG. Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors. Int J Mol Sci 2022; 23:13612. [PMID: 36362398 PMCID: PMC9655697 DOI: 10.3390/ijms232113612] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/31/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
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Affiliation(s)
- Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Myrto Trifylli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Evangelos Koustas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Comparing T Cell Subsets in Broncho-Alveolar Lavage (BAL) and Peripheral Blood in Patients with Advanced Lung Cancer. Cells 2022; 11:cells11203226. [PMID: 36291098 PMCID: PMC9600421 DOI: 10.3390/cells11203226] [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: 08/11/2022] [Revised: 10/03/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.
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Mastracci L, Grillo F, Parente P, Gullo I, Campora M, Angerilli V, Rossi C, Sacramento ML, Pennelli G, Vanoli A, Fassan M. PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application. Pathologica 2022; 114:352-364. [PMID: 36305021 PMCID: PMC9614301 DOI: 10.32074/1591-951x-803] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma). In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.
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Affiliation(s)
- Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Portugal
- i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
| | - Michela Campora
- Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Department of Laboratory Medicine, Pathology Unit, Trento, Italy
| | - Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Chiara Rossi
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Maria Luisa Sacramento
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Gianmaria Pennelli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua (PD), Italy
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Sommer U, Ebersbach C, Beier AMK, Baretton GB, Thomas C, Borkowetz A, Erb HHH. Influence of Androgen Deprivation Therapy on the PD-L1 Expression and Immune Activity in Prostate Cancer Tissue. Front Mol Biosci 2022; 9:878353. [PMID: 35836932 PMCID: PMC9273856 DOI: 10.3389/fmolb.2022.878353] [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: 02/17/2022] [Accepted: 05/17/2022] [Indexed: 12/19/2022] Open
Abstract
Immune checkpoint inhibitors have become a promising new therapy for cancer treatment. However, due to prostate cancer’s high heterogeneity and immune-suppressive tumour microenvironment, clinical trials with immune checkpoint inhibitors for prostate cancer resulted in low or no response. This descriptive and retrospective study investigates the influence of androgen deprivation therapy (ADT) on PD-L1 expression and CD8+ T-cell tumour infiltration and activity in primary prostate cancer tissue. Therefore, immunohistochemistry was used to assess PD-L1, CD8+ T-cell, and the immune activation marker Granzyme B (GrB) in PCa tissue before and under ADT. In line with previous studies, few prostate cancer tissues showed PD-L1 expression and CD8+ T-cell infiltration. However, PD-L1 expression levels on tumour cells or infiltrating immune cells above 5% generated an immune-suppressive tumour microenvironment harbouring hypofunctional CD8+ T-cells. Moreover, analysis of a longitudinal patient cohort before and under ADT revealed that ADT increased hypofunctional CD8+ T cells in the tumour area suggesting a tumour immune milieu optimal for targeting with immunotherapy.
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Affiliation(s)
- Ulrich Sommer
- Institute of Pathology, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
- National Center for Tumor Diseases Partner Site Dresden and German Cancer Center Heidelberg, Dresden, Germany
- Tumor and Normal Tissue Bank of the University Cancer Center (UCC), University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Ulrich Sommer, ; Holger H. H. Erb,
| | - Celina Ebersbach
- Department of Urology, Technische Universität Dresden, Dresden, Germany
- Department of Urology, Mildred Scheel Early Career Center, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Alicia-Marie K. Beier
- Department of Urology, Technische Universität Dresden, Dresden, Germany
- Department of Urology, Mildred Scheel Early Career Center, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Gustavo B. Baretton
- Institute of Pathology, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
- National Center for Tumor Diseases Partner Site Dresden and German Cancer Center Heidelberg, Dresden, Germany
- Tumor and Normal Tissue Bank of the University Cancer Center (UCC), University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Christian Thomas
- National Center for Tumor Diseases Partner Site Dresden and German Cancer Center Heidelberg, Dresden, Germany
- Department of Urology, Technische Universität Dresden, Dresden, Germany
| | | | - Holger H. H. Erb
- Department of Urology, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Ulrich Sommer, ; Holger H. H. Erb,
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Zhang X, Wang S, Nie RC, Qu C, Chen J, Yang Y, Cai M. Immune Microenvironment Characteristics of Urachal Carcinoma and Its Implications for Prognosis and Immunotherapy. Cancers (Basel) 2022; 14:cancers14030615. [PMID: 35158883 PMCID: PMC8833550 DOI: 10.3390/cancers14030615] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Urachal carcinoma (UrC) is an exceedingly rare tumor and lacks effective treatment. Herein, we characterized an immune microenvironment characteristic of UrC in detail and identified its implications for prognosis and immunotherapy. In total, 37 resections of UrC were stained for CD20, CD3, CD4, CD8, FOXP3, CD68, HLA-DR, CD163, PD1, and PD-L1, as well as mismatch repair protein including MSH2, MSH6, MLH1, and PMS2 by immunohistochemistry. Intratumoral and peritumoral immune cell densities or the proportion of PD1 and PD-L1 expression alongside MSH2, MSH6, MLH1, and PMS2 status were manually evaluated using the whole slide. UrC patients with the number of tertiary lymphoid structures (TLS) per slide tended to be higher in tumors with dMMR (p = 0.1919), and tumors with higher number of TLS tended to have longer OS (p = 0.0940) and DFS (p = 0.0700). High densities of CD3+ T, CD8+ T, and CD68+ cells were significantly associated with worse OS and DFS (both p<0.05). Increased intratumoral (p = 0.0111) and peritumoral (p = 0.0485) CD8+ T cell densities were significantly associated with PD-L1 expression or increasing proportion of PD-L1 expression on immune cells. Similarly, increased intratumoral (p = 0.0008) and peritumoral (p = 0.063) CD8+ T cell densities were significantly associated with increasing proportion of PD1 expression on immune cells. Tumors with PD-L1 positive expression on immune cells had a significantly increased proportion of PD1 expression (p = 0.0121). High peritumoral CD8+ T cell density (>73.7/mm2) was significantly associated with worse OS (p = 0.0120) and DFS (p = 0.00095). The number of TLS seems to be considered not only as histopathological characteristics in predicting MMR status of UrC, but also as a prognostic or therapeutic biomarker, and we also provide some important suggestions for targeting PD-1/PD-L1 checkpoint in UrC.
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Affiliation(s)
- Xinke Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
| | - Suijing Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
| | - Run-Cong Nie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
| | - Chunhua Qu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
| | - Jierong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
| | - Yuanzhong Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
- Correspondence: (Y.Y.); (M.C.); Tel.: +86-20-8734-2274 (M.C.)
| | - Muyan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (X.Z.); (S.W.); (R.-C.N.); (C.Q.); (J.C.)
- Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou 510080, China
- Correspondence: (Y.Y.); (M.C.); Tel.: +86-20-8734-2274 (M.C.)
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