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Mathiesen H, Juul-Madsen K, Tramm T, Vorup-Jensen T, Møller HJ, Etzerodt A, Andersen MN. Prognostic value of CD163 + macrophages in solid tumor malignancies: A scoping review. Immunol Lett 2025; 272:106970. [PMID: 39778658 DOI: 10.1016/j.imlet.2025.106970] [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: 11/12/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Tumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163+ TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163+ TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163+ cells was associated with poor patient outcome, and this association was more frequently observed when CD163+ cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163+ TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163+ TAMs as targets of future immunotherapies.
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Affiliation(s)
- Henriette Mathiesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Juul-Madsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
| | - Trine Tramm
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger Jon Møller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Morten Nørgaard Andersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
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Dai Y, Dong C, Wang Z, Zhou Y, Wang Y, Hao Y, Chen P, Liang C, Li G. Infiltrating T lymphocytes and tumor microenvironment within cholangiocarcinoma: immune heterogeneity, intercellular communication, immune checkpoints. Front Immunol 2025; 15:1482291. [PMID: 39845973 PMCID: PMC11750830 DOI: 10.3389/fimmu.2024.1482291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection and systemic chemotherapy have traditionally been the standard treatment options. However, the complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical treatment and resistance to late-stage chemotherapy limit the benefits for patients. Immunotherapy has emerged as an effective strategy for treating various types of cancer, and has shown efficacy when combined with chemotherapy for cholangiocarcinoma. Current immunotherapies targeting cholangiocarcinoma have predominantly focused on T lymphocytes within the tumor microenvironment, and new immunotherapies have yielded unsatisfactory results in clinical trials. Therefore, it is essential to achieve a comprehensive understanding of the unique tumor microenvironment of cholangiocarcinoma and the pivotal role of T lymphocytes within it. In this review, we describe the heterogeneous immune landscape and intercellular communication in cholangiocarcinoma and summarize the specific distribution of T lymphocytes. Finally, we review potential immune checkpoints in cholangiocarcinoma.
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Affiliation(s)
- Yunyan Dai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Chenyang Dong
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zhiming Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yunpeng Zhou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yi Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yi Hao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Pinggui Chen
- Department of Nuclear Medicine, Nanyang First People’s Hospital, Nanyang, Henan, China
| | - Chaojie Liang
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
- Department of biliary and Pancreatic Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Gaopeng Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China
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Laface C, Fina E, Ricci AD, Guven DC, Ambrogio F, De Summa S, Vitale E, Massafra R, Brunetti O, Rizzo A. Immunobiology of biliary tract cancer and recent clinical findings in approved and upcoming immune checkpoint inhibitors. Expert Opin Biol Ther 2024; 24:1363-1374. [PMID: 39545466 DOI: 10.1080/14712598.2024.2431088] [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: 08/01/2024] [Revised: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 11/17/2024]
Abstract
INTRODUCTION Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches. AREAS COVERED In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials. EXPERT OPINION At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.
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Affiliation(s)
- Carmelo Laface
- Azienda Sanitaria Provinciale, Reggio Calabria (RC), Italy
| | - Emanuela Fina
- Thoracic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS "S. de Bellis" Research Hospital, Castellana Grotte, Italy
| | - Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
- Medical Oncology Clinic, Elazig City Hospital, Health Sciences University, Elazig, Turkey
| | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
| | - Simona De Summa
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori, "Giovanni Paolo II", Bari, Italy
| | - Elsa Vitale
- Scientific Directorate, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Raffaella Massafra
- Scientific Directorate, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Oronzo Brunetti
- S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Alessandro Rizzo
- S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
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Toprak V, Özdemir İ, Öztürk Ş, Yanar O, Kizildemir YZ, Tuncer MC. Modulation of FOXP3 Gene Expression in OVCAR3 Cells Following Rosmarinic Acid and Doxorubicin Exposure. Pharmaceuticals (Basel) 2024; 17:1606. [PMID: 39770446 PMCID: PMC11676701 DOI: 10.3390/ph17121606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Ovarian cancer has the highest mortality rate in the world. Treatment methods are listed as surgery, chemotherapy, and radiotherapy, depending on the stage of cancer, but developing resistance to chemotherapy increases the need for alternative agents that act on the same pathways. The effects of rosmarinic acid (RA) and doxorubicin (DX) on the activation of FOXP3, an important tumor suppressor gene, in OVCAR3 cells were examined. Materials and Methods: In this study, a human ovarian adenocarcinoma cell line was used. MTT analysis was performed to reveal the result of RA and DX on ovarian cancer cell proliferation. Expression levels of FOXP3 for cell proliferation and Capase-3 for apoptosis were determined by RT-qPCR. The wound healing model was applied to determine cell migration rates. The results were evaluated with one-way ANOVA in an SPSS 20.0 program as p ≤ 0.05. Results: It was determined that RA and DX alone and in combination inhibited the proliferation of OVCAR3 cells in different doses for 24, 48, and 72 h, and caused the cells to die by causing them to undergo apoptosis. Caspase-3 expression increased approximately tenfold in OVCAR3 cells, while FOXP3 expression was upregulated only in RA treatment and was downregulated in DX and RA + DX treatments. Conclusions: According to the results of our study, it was determined that the FOXP3 signaling pathway related to apoptosis, and proliferation was affected by the combination treatment of RA and DX in the OVCAR3 cancer cell line. This shows that RA will gain an important place in cancer treatment with more comprehensive study.
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Affiliation(s)
- Veysel Toprak
- Private Metrolife Hospital, Şanlıurfa 63320, Turkey;
| | - İlhan Özdemir
- Department of Gynecology and Obstetrics, Faculty of Medicine, Atatürk University, Erzurum 25070, Turkey;
| | - Şamil Öztürk
- Vocational School of Health Services, Çanakkale Onsekiz Mart University, Çanakkale 17100, Turkey;
| | - Orhan Yanar
- Private Nev Hospital, Şanlıurfa 63300, Turkey;
| | | | - Mehmet Cudi Tuncer
- Department of Anatomy, Faculty of Medicine, Dicle University, Diyarbakir 21200, Turkey
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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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Wirta EV, Szeto S, Koppatz H, Nordin A, Mäkisalo H, Arola J, Sirén J, Ahtiainen M, Böhm J, Mecklin JP, Sallinen V, Seppälä TT. High immune cell infiltration predicts improved survival in cholangiocarcinoma. Front Oncol 2024; 14:1333926. [PMID: 38751812 PMCID: PMC11094285 DOI: 10.3389/fonc.2024.1333926] [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: 11/14/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024] Open
Abstract
Background Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumor-infiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis. Methods CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells. Results Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup. Conclusion Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy.
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Affiliation(s)
- Erkki-Ville Wirta
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland
| | - Säde Szeto
- Applied Tumor Genomics Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hanna Koppatz
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Arno Nordin
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Heikki Mäkisalo
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jukka Sirén
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Maarit Ahtiainen
- Department of Molecular Pathology, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
| | - Jan Böhm
- Department of Molecular Pathology, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Science, Central Finland Hospital Nova, Well Being Services County of Central Finland, Jyväskylä, Finland
- Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Ville Sallinen
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Toni T. Seppälä
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere University Hospital, Tampere, Finland
- Applied Tumor Genomics Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Abdominal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Zhou X, Zhang B, Hu J, Shen J, Chen Z, Zhang J, Wu B, Zhou E, Peng S, Wong TW, Yang G, Cao J, Chen M. Igniting cold tumors of intrahepatic cholangiocarcinoma: An insight into immune evasion and tumor immune microenvironment. THE INNOVATION MEDICINE 2024; 2:100052. [DOI: 10.59717/j.xinn-med.2024.100052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
<p>Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer that originates from the epithelium of the intrahepatic bile duct. The various treatments for ICC, such as chemotherapy, radiotherapy, and locoregional therapy, confer only modest improvements in survival rates. Immunotherapy, although revolutionary in cancer treatment, has found limited application in the treatment of ICCs due to the “cold” nature of these tumors, which is marked by scant T-cell infiltration. This characteristic makes immune checkpoint inhibitors (ICIs) unsuitable for the majority of ICC patients. Therefore, comprehensively understanding the mechanisms underlying these “cold” tumors is crucial for harnessing the potential of immunotherapy for treating ICC patients. This paper explores immune evasion mechanisms and the complex tumor immune microenvironment of ICC. This study provides a comprehensive overview of therapeutic strategies aimed at activating cold tumors and enhancing their immunogenicity. Furthermore, potential and promising targets for cancer vaccines and adoptive cellular therapy in the context of ICC are discussed. This endeavor strives to reveal new pathways for innovative immunotherapy strategies, with a focus on overcoming the key challenge of triggering an effective immune response in ICC patients.</p>
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Li C, Bie L, Chen M, Ying J. Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1310-1327. [PMID: 38213535 PMCID: PMC10776604 DOI: 10.37349/etat.2023.00199] [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: 08/01/2023] [Accepted: 10/09/2023] [Indexed: 01/13/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive type of adenocarcinoma distinguished by its invasiveness. Depending on specific anatomical positioning within the biliary tree, CCA can be categorized into intrahepatic CCA (ICCA), perihilar CCA (pCCA) and distal CCA (dCCA). In recent years, there has been a significant increase in the global prevalence of CCA. Unfortunately, many CCA patients are diagnosed at an advanced stage, which makes surgical resection impossible. Although systemic chemotherapy is frequently used as the primary treatment for advanced or recurrent CCA, its effectiveness is relatively low. Therefore, immunotherapy has emerged as a promising avenue for advancing cancer treatment research. CCA exhibits a complex immune environment within the stromal tumor microenvironment (TME), comprising a multifaceted immune landscape and a tumor-reactive stroma. A deeper understanding of this complex TME is indispensable for identifying potential therapeutic targets. Thus, targeting tumor immune microenvironment holds promise as an effective therapeutic strategy.
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Affiliation(s)
- Chaoqun Li
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou 310022, Zhejiang, China
| | - Lei Bie
- Department of Thoracic Surgery, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Muhua Chen
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
| | - Jieer Ying
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China
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Cai P, Wu Z, Yang X, Wang N, Yang Y. The prognostic value of Forkhead box P3 regulatory T cells in biliary tract cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e36608. [PMID: 38115302 PMCID: PMC10727656 DOI: 10.1097/md.0000000000036608] [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: 06/22/2023] [Revised: 11/19/2023] [Accepted: 11/21/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND This study aimed to explore the value of tumor-infiltrating Forkhead box P3(FoxP3+) regulatory T cells (Tregs) in evaluating the prognosis of biliary tract cancer. METHODS Four electronic databases were searched using 2 computers: PubMed, Embase, Web of Science, and Cochrane Library. The vocabulary and syntax were adapted according to the database. Two researchers independently selected the studies, collected information, and assessed the risk of bias. The Meta-analysis was performed using STATA 17.0, and HR and its corresponding 95% CI were used to evaluate the correlation between FoxP3+ Tregs and the overall survival of patients with biliary tract cancer. In addition, the quality of the included studies was evaluated. RESULTS Ten articles were included in this study. The results of the meta-analysis showed that patients with high FoxP3+ Tregs infiltration had worse overall survival (OS) (HR = 1.34,95% CI 1.16 to 1.71; P < .001). Subgroup analysis of gallbladder carcinoma and cholangiocarcinoma showed that the high infiltration of FoxP3+ Tregs was significantly correlated with the OS of the former (HR = 1.55,95% CI 1.11 to 2.00; P < .001), but not with the OS of the latter (HR = 1.00,95% CI 0.62 to 1.38; P > .05). CONCLUSIONS Our meta-analysis reveals that high infiltration of FoxP3 + Tregs is significantly associated with reduced overall survival in gallbladder carcinoma, endorsing their use as a prognostic biomarker for this subtype. In contrast, no significant prognostic correlation was identified for FoxP3+ Tregs in cholangiocarcinoma, indicating the need for subtype-specific evaluation of their prognostic relevance in biliary tract cancers.
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Affiliation(s)
- Pengcheng Cai
- Department of General Surgery, the First People’s Hospital of Shuangliu District, Chengdu, Sichuan Province, China
| | - Zhongli Wu
- Department of General Surgery, the First People’s Hospital of Shuangliu District, Chengdu, Sichuan Province, China
| | - Xingjian Yang
- Department of General Surgery, the First People’s Hospital of Shuangliu District, Chengdu, Sichuan Province, China
| | - Na Wang
- Department of General Surgery, the First People’s Hospital of Shuangliu District, Chengdu, Sichuan Province, China
| | - Yong Yang
- Department of General Surgery, the First People’s Hospital of Shuangliu District, Chengdu, Sichuan Province, China
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Gehl V, O'Rourke CJ, Andersen JB. Immunogenomics of cholangiocarcinoma. Hepatology 2023:01515467-990000000-00649. [PMID: 37972940 DOI: 10.1097/hep.0000000000000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/16/2023] [Indexed: 11/19/2023]
Abstract
The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.
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Affiliation(s)
- Virag Gehl
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
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11
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Okami H, Ozawa N, Sohda M, Yokobori T, Osone K, Erkhem-Ochir B, Dorjkhorloo G, Shiraishi T, Okada T, Sano A, Sakai M, Miyazaki T, Ogawa H, Yao T, Oike T, Sato H, Shirabe K, Shibata A, Saeki H. HLA Class I Expression Is Associated with DNA Damage and Immune Cell Infiltration into Dysplastic and Neoplastic Lesions in Ulcerative Colitis. Int J Mol Sci 2023; 24:13648. [PMID: 37686454 PMCID: PMC10487850 DOI: 10.3390/ijms241713648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/24/2023] [Accepted: 09/02/2023] [Indexed: 09/10/2023] Open
Abstract
Human leukocyte antigen class I (HLA-I) is considered a genetic pathogen for ulcerative colitis (UC). This study aimed to investigate the significance of DNA damage and HLA-I expression in infiltrating immune cells and immune checkpoint protein PD-L1 expression in dysplasia/colitic cancer (CC) and sporadic colorectal cancer (SCRC). We performed immunohistochemical staining for HLA-I, PD-L1, γH2AX (DNA damage marker), and immune cell markers such as CD8, FOXP3, CD68, and CD163 (in surgically resected specimens from 17 SCRC patients with 12 adjacent normal mucosa (NM) and 9 UC patients with 18 dysplasia/CC tumors. The ratio of membrane HLA-I-positive epithelial cells in UC and dysplasia/CC tissues was significantly higher than that in NM and SCRC. High HLA-I expression in dysplasia/CC was associated with high positivity of γH2AX and PD-L1 expression compared to SCRC. The infiltration of CD8-positive T cells and CD68-positive macrophages in HLA-I-high dysplasia/CC was significantly higher than in UC and SCRC. Dysplasia/CC specimens with DNA damage exhibited high levels of HLA-I-positive epithelial cells with high CD8- and CD68-positive immune cell infiltration compared to UC and SCRC specimens. Targeting DNA damage in UC may regulate immune cell infiltration, immune checkpoint proteins, and carcinogenesis by modulating DNA damage-induced HLA-I antigen presentation.
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Affiliation(s)
- Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Naoya Ozawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan;
| | - Katsuya Osone
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Bilguun Erkhem-Ochir
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan;
| | - Gendensuren Dorjkhorloo
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Takuya Shiraishi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Takuhisa Okada
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Tatsuya Miyazaki
- Department of Surgery Japanese Red Cross Maebashi Hospital, Maebashi 371-0811, Japan;
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Takashi Yao
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Bunkyo-ku 113-8431, Japan;
| | - Takahiro Oike
- Department of Radiation Oncology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (T.O.); (H.S.)
| | - Hiro Sato
- Department of Radiation Oncology, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (T.O.); (H.S.)
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
| | - Atsushi Shibata
- Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Minato-ku 108-8345, Japan;
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan; (H.O.); (N.O.); (K.O.); (G.D.); (T.S.); (T.O.); (A.S.); (M.S.); (H.O.); (K.S.); (H.S.)
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12
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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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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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14
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Jin Z, Liu YH. Metabolic-related gene signatures for survival prediction and immune cell subtypes associated with prognosis in intrahepatic cholangiocarcinoma. Cancer Genet 2023; 274-275:84-93. [PMID: 37099969 DOI: 10.1016/j.cancergen.2023.04.001] [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: 02/15/2023] [Revised: 03/26/2023] [Accepted: 04/11/2023] [Indexed: 04/28/2023]
Abstract
OBJECTIVES Our study aimed to reveal the metabolic-related gene signatures for survival prediction and immune cell subtypes associated with IHCC prognosis. METHODS Differentially expressed metabolic genes were identified between survival group and dead group which were divided according to survival at discharge. Recursive feature elimination (RFE) and randomForest (RF) algorithms were applied to optimize the combination of feature metabolic genes, which were used to generate SVM classifier. Performance of SVM classifier was evaluated by receiver operating characteristic (ROC) curves. Gene set enrichment analysis (GSEA) was conducted to uncover the activated pathways in high risk group, and differences in immune cell distributions were revealed. RESULTS There were 143 differentially expressed metabolic gens. RFE and RF identified 21 overlapping differentially expressed metabolic genes, and the constructed SVM classifier had excellent accuracy in training and validation dataset. RS survival prediction model was consisted of 10 metabolic genes. RS model had reliable predictive capability in the training and validation dataset. GSEA revealed 15 significant KEGG pathways that were relatively activated in the high risk group. High risk group had obviously lower counts of B cell naive and T cell CD4+ memory resting, while higher counts of B cell plasma and macrophage M2. CONCLUSION Prognostic prediction model of 10 metabolic genes could accurately predict the prognosis of IHCC patients.
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Affiliation(s)
- Zhe Jin
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, No. 1, Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China
| | - Ya-Hui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, No. 1, Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China.
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15
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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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16
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Brummel K, Eerkens AL, de Bruyn M, Nijman HW. Tumour-infiltrating lymphocytes: from prognosis to treatment selection. Br J Cancer 2023; 128:451-458. [PMID: 36564565 PMCID: PMC9938191 DOI: 10.1038/s41416-022-02119-4] [Citation(s) in RCA: 117] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Tumour-infiltrating lymphocytes (TILs) are considered crucial in anti-tumour immunity. Accordingly, the presence of TILs contains prognostic and predictive value. In 2011, we performed a systematic review and meta-analysis on the prognostic value of TILs across cancer types. Since then, the advent of immune checkpoint blockade (ICB) has renewed interest in the analysis of TILs. In this review, we first describe how our understanding of the prognostic value of TIL has changed over the last decade. New insights on novel TIL subsets are discussed and give a broader view on the prognostic effect of TILs in cancer. Apart from prognostic value, evidence on the predictive significance of TILs in the immune therapy era are discussed, as well as new techniques, such as machine learning that strive to incorporate these predictive capacities within clinical trials.
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Affiliation(s)
- Koen Brummel
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands
| | - Anneke L Eerkens
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands
| | - Marco de Bruyn
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands
| | - Hans W Nijman
- University of Groningen, University Medical Center Groningen, Department of Obstetrics and Gynecology, Groningen, The Netherlands.
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17
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Yu X, Zhu L, Wang T, Chen J. Immune microenvironment of cholangiocarcinoma: Biological concepts and treatment strategies. Front Immunol 2023; 14:1037945. [PMID: 37138880 PMCID: PMC10150070 DOI: 10.3389/fimmu.2023.1037945] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies.
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Affiliation(s)
- Xianzhe Yu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Gastrointestinal Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Lingling Zhu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ting Wang
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiang Chen
- Department of General Surgery, Sir Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Jiang Chen,
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18
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Carloni R, Rizzo A, Ricci AD, Federico AD, De Luca R, Guven DC, Yalcin S, Brandi G. Targeting tumor microenvironment for cholangiocarcinoma: Opportunities for precision medicine. Transl Oncol 2022; 25:101514. [PMID: 35977458 PMCID: PMC9396390 DOI: 10.1016/j.tranon.2022.101514] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/27/2022] Open
Abstract
CCA has a dismal prognosis, and it is usually diagnosed in advanced stage for which available treatments have limited efficacy. CCA TME presents an abundant desmoplastic stroma and exhibits a high heterogeneity. TME plays a central role in cancer development and in the resistance to treatments. Treatments targeting the TME in association with cytotoxic agents could represent a promising therapeutic strategy. Systemic treatments (e.g., chemotherapy and targeted therapies) have limited efficacy for patients with locally advanced – unresectable – and metastatic cholangiocarcinoma (CCA), with an overall survival of less than a year. Tumor microenvironment (TME) represents the ecosystem surrounding the tumor which comprises immune cells, fibroblasts, endothelial cells, and a wide range of soluble factors. CCA TME is characterized by an abundant desmoplastic stroma, exhibits a high heterogeneity and it plays a central role in cancer onset and progression. There is growing evidence suggesting that it is possible to target TME in association with other treatment modalities, such as cytotoxic chemotherapy or targeted therapies, paving the way to possible combination strategies with a synergistic effect. Herein, we describe the components of CCA TME – such as cancer-associated fibroblasts and other cells of pivotal importance - with their most relevant interactions, focusing on the preclinical rationale for the development of effective anticancer treatments.
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Affiliation(s)
- Riccardo Carloni
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, Bologna 40138, Italy; Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, Bologna 40138, Italy
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico "Don Tonino Bello", I.R.C.C.S. Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, Bari 70124, Italy.
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, "Saverio de Bellis" Research Hospital, Castellana Grotte, Italy
| | - Alessandro Di Federico
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, Bologna 40138, Italy; Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, Bologna 40138, Italy
| | - Raffaele De Luca
- Department of Surgical Oncology, IRCCS Istituto Tumori " Giovanni Paolo ", Bari, Italy
| | - Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Giovanni Brandi
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, Bologna 40138, Italy; Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, Bologna 40138, Italy
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19
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Kosai‑Fujimoto Y, Itoh S, Yugawa K, Fukuhara T, Okuzaki D, Toshima T, Harada N, Oda Y, Yoshizumi T, Mori M. Impact of JMJD6 on intrahepatic cholangiocarcinoma. Mol Clin Oncol 2022; 17:131. [PMID: 35911665 PMCID: PMC9326512 DOI: 10.3892/mco.2022.2564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022] Open
Abstract
The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarcinoma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.
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Affiliation(s)
- Yukiko Kosai‑Fujimoto
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shinji Itoh
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kyohei Yugawa
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Takasuke Fukuhara
- Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060‑8638, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565‑0871, Japan
| | - Takeo Toshima
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Noboru Harada
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Masaki Mori
- Department of Surgery and Science, School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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20
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Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. Br J Cancer 2022; 127:757-765. [PMID: 35597869 PMCID: PMC9381563 DOI: 10.1038/s41416-022-01838-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Background Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. Methods Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. Results Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher’s exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann–Whitney U test). Conclusions FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.
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21
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Liu D, Heij LR, Czigany Z, Dahl E, Lang SA, Ulmer TF, Luedde T, Neumann UP, Bednarsch J. The role of tumor-infiltrating lymphocytes in cholangiocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:127. [PMID: 35392957 PMCID: PMC8988317 DOI: 10.1186/s13046-022-02340-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/23/2022] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients. In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA. In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translational data is needed to fully unravel the importance of TILs in the treatment of CCA.
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Affiliation(s)
- Dong Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Lara Rosaline Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Heinrich Heine University Duesseldorf, Duesseldorf, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. .,Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
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22
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Monge C, Pehrsson EC, Xie C, Duffy AG, Mabry D, Wood BJ, Kleiner DE, Steinberg SM, Figg WD, Redd B, Budhu A, Wang S, Tandon M, Ma L, Wei Wang X, Greten TF. A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma. Oncologist 2022; 27:e273-e285. [PMID: 35274717 PMCID: PMC8914487 DOI: 10.1093/oncolo/oyab073] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/07/2021] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. PATIENTS AND METHODS Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. RESULTS Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. CONCLUSION Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. TRIAL REGISTRATION This study was registered in ClinicalTrials.gov (NCT03111732).
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Affiliation(s)
- Cecilia Monge
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Erica C Pehrsson
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Changqing Xie
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Austin G Duffy
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Donna Mabry
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bradford J Wood
- Center for Interventional Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - David E Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - William D Figg
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bernadette Redd
- Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anuradha Budhu
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sophie Wang
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mayank Tandon
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Lichun Ma
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xin Wei Wang
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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23
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Immune Score Predicts Outcomes of Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy. JOURNAL OF ONCOLOGY 2022; 2021:9344124. [PMID: 34987582 PMCID: PMC8723845 DOI: 10.1155/2021/9344124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023]
Abstract
Background Substantial evidence has demonstrated that tumor-infiltrating lymphocytes (TILs) are correlated with patient prognosis. The TIL-based immune score (IS) affects prognosis in various cancers, but its prognostic impact in gastric cancer (GC) patients treated with adjuvant chemoradiotherapy remains unclear. Methods A total of 101 GC patients who received chemoradiotherapy after gastrectomy were retrospectively analyzed in this study. Immunohistochemistry staining for CD3+ and CD8+ T-cell counts in both tumor center (CT) and invasive margin (IM) regions was built into the IS. Patients were then divided into three groups based on their differential IS levels. The correlation between IS and clinical parameters was analyzed. The prognostic impact of IS and clinical parameters was evaluated using Kaplan-Meier analysis and Cox proportional hazard regression analysis. Receiver operating characteristic (ROC) curves were plotted to compare the area under the curve (AUC) of IS with other clinical parameters. Nomograms for disease-free survival (DFS) and overall survival (OS) prediction were constructed based on the identified parameters. Results Finally, 20 (19.8%), 57 (56.4%), and 24 (23.8%) GC patients were identified with low, intermediate, and high IS levels, respectively. GC patients with higher IS levels exhibited better DFS (p < 0.001) and OS (p < 0.001). IS was an independent prognostic factor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. IS presented a better predictive ability than the traditional pathological tumor-node-metastasis (pTNM) staging system (AUC: 0.801 vs. 0.677 and 0.800 vs. 0.660, respectively) with respect to both DFS and OS. The C-index of the nomograms for DFS and OS prediction was 0.737 and 0.774, respectively. Conclusions IS is a strong predictive factor for both DFS and OS in GC patients treated with adjuvant chemoradiotherapy, which may complement the traditional pTNM staging system.
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24
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Ran X, Luo J, Zuo C, Huang Y, Sui Y, Cen J, Tang S. Developing metabolic gene signatures to predict intrahepatic cholangiocarcinoma prognosis and mining a miRNA regulatory network. J Clin Lab Anal 2021; 36:e24107. [PMID: 34871464 PMCID: PMC8761474 DOI: 10.1002/jcla.24107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 11/10/2022] Open
Abstract
Background Metabolic disturbance is closely correlated with intrahepatic cholangiocarcinoma (IHCC), and we aimed to identify metabolic gene marker for the prognosis of IHCC. Methods We obtained expression and clinical data from 141 patients with IHCC from public databases. Prognostic metabolic genes were selected using univariate Cox regression analysis. Unsupervised cluster analysis was applied to identify IHCC subtypes, and CIBERSORT was used for immune infiltration analysis of different subtypes. Then, the metabolic gene signature was screened using multivariate Cox regression analysis and the LASSO algorithm. The prognostic potential and regulatory network of the metabolic gene signature were further investigated. Results We screened 228 prognosis‐related metabolic genes. Based on their expression levels, IHCC samples were divided into two subtypes, which showed significant differences in survival and immune cell infiltration. After LASSO analysis, eight metabolic genes including CYP19A1, SCD5, ACOT8, SRD5A3, MOGAT2, PFKFB3, PPARGC1B, and RPL17 were identified as the optimal genes for the prognosis signature. The prognostic model had excellent predictive abilities, with areas under the receiver‐operating characteristic curves over 0.8. A nomogram model was also established based on two independent prognostic clinical factors (pathologic stage and prognostic model), and the generated calibration curves and c‐indexes determined its excellent accuracy and discriminative ability to predict 1‐ and 5‐year survival status (c‐indexes>0.7). Finally, we found that miR‐26a‐5p, miR‐27a‐3p, and miR‐27b‐3p were the upstream regulators that mediate the involvement of gene signatures in metabolic pathways. Conclusion We developed eight metabolic gene signatures to predict IHCC prognosis and proposed potential upstream regulatory axes of gene signatures.
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Affiliation(s)
- Xun Ran
- Department of hepatobiliary surgery, The affiliated hospital of Guizhou medical university, Guiyang, Guizhou Province, China
| | - Jun Luo
- Department of hepatobiliary surgery, The affiliated hospital of Guizhou medical university, Guiyang, Guizhou Province, China
| | - Chaohai Zuo
- Department of Hepatobiliary Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong Province, China
| | - YongYe Huang
- Digestive center area two, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Yi Sui
- IVD Medical Marketing Department, 3D Medicine Inc., Shanghai, China
| | - JunHua Cen
- Hepatobiliary Surgery Department, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Shengli Tang
- Hepatopancreatobiliary surgery, Zhongnan hospital of Wuhan university, Wuhan, Hubei, China
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25
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Tsimafeyeu I, Temper M. Cholangiocarcinoma: An Emerging Target for Molecular Therapy. Gastrointest Tumors 2021; 8:153-158. [PMID: 34722468 DOI: 10.1159/000517258] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/18/2021] [Indexed: 12/30/2022] Open
Abstract
Background Cholangiocarcinoma has been traditionally considered a tumor with poor prognosis. Until now, surgical treatment has been the only more or less effective approach. Summary Over 10 years, chemotherapy with a combination of gemcitabine and cisplatin remains the standard first-line therapy for patients with locally advanced or metastatic cholangiocarcinoma, which leads to a median overall survival of 11.7 months. Several inhibitors of HER (ERBB), HGF/c-MET, Hedgehog, KRAS-BRAF-MEK-ERK, and PI3K/AKT/mTOR signaling pathways did not show their superiority to standard chemotherapy. The rise of hope is associated with the emergence of novel fibroblast growth factor receptors and isocitrate dehydrogenase inhibitors as well as immune checkpoint inhibitors.
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Affiliation(s)
- Ilya Tsimafeyeu
- Institute of Oncology, Hadassah Moscow, Moscow, Russian Federation
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26
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Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma. Br J Cancer 2021; 126:219-227. [PMID: 34616011 DOI: 10.1038/s41416-021-01569-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/04/2021] [Accepted: 09/27/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. METHODS Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. RESULTS CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. CONCLUSION Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.
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27
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Miyazaki K, Morine Y, Yamada S, Saito Y, Tokuda K, Okikawa S, Yamashita S, Oya T, Ikemoto T, Imura S, Hu H, Morioka H, Tsuneyama K, Shimada M. Stromal tumor-infiltrating lymphocytes level as a prognostic factor for resected intrahepatic cholangiocarcinoma and its prediction by apparent diffusion coefficient. Int J Clin Oncol 2021; 26:2265-2274. [PMID: 34596803 DOI: 10.1007/s10147-021-02026-3] [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: 05/09/2021] [Accepted: 08/09/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Tumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs. METHODS We enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients' clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value. RESULTS Stromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02). CONCLUSIONS Stromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue.
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Affiliation(s)
- Katsuki Miyazaki
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kazunori Tokuda
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shohei Okikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shoko Yamashita
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.,Department of Pathology and Laboratory Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Takeshi Oya
- Department of Molecular Pathology, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Satoru Imura
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Haun Hu
- Department of Public Health, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hisayoshi Morioka
- Department of Public Health, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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28
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Charalampakis N, Papageorgiou G, Tsakatikas S, Fioretzaki R, Kole C, Kykalos S, Tolia M, Schizas D. Immunotherapy for cholangiocarcinoma: a 2021 update. Immunotherapy 2021; 13:1113-1134. [PMID: 34190581 DOI: 10.2217/imt-2021-0126] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.
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Affiliation(s)
- Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus, 185 37, Greece
| | - Christo Kole
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Stylianos Kykalos
- Second Propedeutic Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Voutes, 71110, Heraklion, Crete, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
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29
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Zhang J, Wu Z, Zhao J, Liu S, Zhang X, Yuan F, Shi Y, Song B. Intrahepatic cholangiocarcinoma: MRI texture signature as predictive biomarkers of immunophenotyping and survival. Eur Radiol 2021; 31:3661-3672. [PMID: 33245493 DOI: 10.1007/s00330-020-07524-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/22/2020] [Accepted: 11/16/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Clinical evidence suggests that the response to immune checkpoint blockade depends on the immune status in the tumor microenvironment. This study aims to predict the immunophenotyping (IP) and overall survival (OS) of intrahepatic cholangiocarcinoma (ICC) patients using preoperative magnetic resonance imaging (MRI) texture analysis. METHODS A total of 78 ICC patients were included and divided into inflamed (n = 26) or non-inflamed (n = 52) immunophenotyping based on the density of CD8+ T cells. The enhanced T1-weighted MRI in the arterial phase was employed with texture analysis. The logistic regression analysis was applied to select the significant features related to IP. The OS-related feature was determined by Cox proportional-hazards model and Kaplan-Meier analysis. IP and OS predictive models were developed using the selected features, respectively. RESULTS Three wavelets and one 3D feature have favorable ability to discriminate IP, a combination of which performed best with an AUC of 0.919. The inflamed immunophenotyping had a better prognosis than the non-inflamed one. The 5-year survival rates of the two groups were 48.5% and 25.3%, respectively (p < 0.05). The only wavelet-HLH_firstorder_Median feature was associated with OS and used to build the OS predictive model with a C-index of 0.70 (95% CI, 0.57, 0.82), which could well stratify ICC patients into high- and low-risk groups. The 1-, 3-, and 5-year survival probabilities of the stratified groups were 62.5%, 30.0%, and 24.2%, and 89.5%, 62.2%, and 42.1%, respectively (p < 0.05). CONCLUSION The MRI texture signature could serve as a potential predictive biomarker for the IP and OS of ICC patients. KEY POINTS • The MRI texture signature, including three wavelets and one 3D feature, showed significant associations with immunophenotyping of ICC, and all have favorable ability to discriminate immunophenotyping; a combination of the above features performed best with an AUC of 0.919. • The only wavelet-HLH_firstorder_Median feature was associated with the OS of ICC and used to build the OS predictive model, which could well stratify ICC patients into high- and low-risk groups.
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Affiliation(s)
- Jun Zhang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenru Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jian Zhao
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Siyun Liu
- Pharmaceutical Diagnostic Team, GE Healthcare, Life Sciences, Beijing, 100176, China
| | - Xin Zhang
- Pharmaceutical Diagnostic Team, GE Healthcare, Life Sciences, Beijing, 100176, China
| | - Fang Yuan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yujun Shi
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Preoperative lymphocyte/C-reactive protein ratio and its correlation with CD8 + tumor-infiltrating lymphocytes as a predictor of prognosis after resection of intrahepatic cholangiocarcinoma. Surg Today 2021; 51:1985-1995. [PMID: 34009433 DOI: 10.1007/s00595-021-02295-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
PURPOSE To clarify whether the preoperative lymphocyte/C-reactive protein (CRP) ratio (LCR) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (IHCC), and investigate its mechanism via tumor-infiltrating lymphocytes. METHODS The subjects of this retrospective study were 42 patients who had undergone hepatectomy for IHCC. We divided the patients into low LCR and high LCR groups (cutoff value: 8780) and analyzed their overall survival (OS) and disease-free survival (DFS) with respect to LCR and other clinicopathological factors. We also investigated the levels of stromal tumor-infiltrating lymphocytes (TILs) and CD8+ TILs in surgical specimens, and the relationship between LCR and TILs. RESULTS A low LCR was identified in 21 patients and was significantly correlated with older age, a high CRP-albumin ratio, and advanced disease stage, and was a prognostic factor for OS and DFS. Multivariate analysis revealed that a low LCR was an independent prognostic factor for worse OS (HR 10.40, P = 0.0077). Although the LCR and levels of stromal TILs were not significantly related, LCR and levels of CD8+ TILs were significantly related (P = 0.0297). CONCLUSION The preoperative LCR may predict the postsurgical prognosis of patients with IHCC and reflect the CD8+ TILs.
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Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes. Mod Pathol 2021; 34:798-807. [PMID: 33077921 DOI: 10.1038/s41379-020-00702-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/18/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = -0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.
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Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status. Sci Rep 2021; 11:5845. [PMID: 33712681 PMCID: PMC7955092 DOI: 10.1038/s41598-021-85186-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 02/26/2021] [Indexed: 12/12/2022] Open
Abstract
Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI < 25.0 kg/m2, n = 48) and obesity groups (BMI ≥ 25.0 kg/m2, n = 26), respectively. Serum carbohydrate antigen 19–9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on 18F-FDG PET/CT (n = 46, r = 0.5152). Patients with high 18F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8 + tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3 + TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.
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Louis C, Edeline J, Coulouarn C. Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy. Expert Opin Ther Targets 2021; 25:153-162. [PMID: 33502260 DOI: 10.1080/14728222.2021.1882998] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 01/26/2021] [Indexed: 02/08/2023]
Abstract
Introduction: Cholangiocarcinoma (CCA) is a rare, deadly cancer that is characterized by an abundant desmoplastic stroma. Late diagnoses and limited available effective treatments are major problems with this malignancy. Targeting of the tumor microenvironment (TME) has emerged as a potential therapeutic strategy.Areas covered: In this review, we describe the role of the various compartments of the TME in CCA and focus on the preclinical rationale for the development of innovative therapies. Relevant literature was identified by a PubMed search covering the last decade (2010-2020).Expert opinion: Low efficacy of surgery and cytotoxic chemotherapy emphasizes the need for new therapeutic strategies and companion biomarkers. Single-cell RNA sequencing of the stroma is yielding a critical functional characterization of TME in CCA and is paving the way for immunotherapies and cancer-associated fibroblast and extracellular matrix-oriented treatments. We believe that the development of treatments targeting the components of the TME will produce the best results if in combination with cytotoxic chemotherapy. Biomarkers should be developed to define the patient population of interest for each combination strategy.
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Affiliation(s)
- Corentin Louis
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre De Lutte Contre Le Cancer Eugène Marquis, Rennes, France
| | - Julien Edeline
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre De Lutte Contre Le Cancer Eugène Marquis, Rennes, France
| | - Cédric Coulouarn
- Inserm, Univ Rennes 1, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, Centre De Lutte Contre Le Cancer Eugène Marquis, Rennes, France
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Wu H, Wei Y, Jian M, Lu H, Song Q, Hao L, Yue Y. Clinicopathological and Prognostic Significance of Immunoscore and PD-L1 in Intrahepatic Cholangiocarcinoma. Onco Targets Ther 2021; 14:39-51. [PMID: 33442265 PMCID: PMC7797318 DOI: 10.2147/ott.s288982] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/18/2020] [Indexed: 12/15/2022] Open
Abstract
Background An increasing amount of evidence reveals that immunosuppression is a major issue in cancer progression. The association of immunoscore (IS) and its impact on clinical outcome have been studied in many tumor types, but its significance in intrahepatic cholangiocarcinoma (ICC) is poorly known. Methods By immunohistochemistry, CD3 and CD8 expressions were assessed in tissue samples of 50 cases of postoperative ICC. The IS was determined by analyzing CD3+ and CD8+ expression data in different areas (intratumor and invasion margins). The relationship between IS and clinicopathological characteristics, including the overall survival (OS) and recurrence-free survival (RFS), was analyzed. In addition, PD-L1, a major regulator of immune escape, was also assessed in tumor cells by immunohistochemistry. Results IS was related to histological differentiation (P=0.026), the presence of lymphoid metastasis (P=0.034), and TNM clinical stages (P = 0.031) of ICC. High IS was significantly associated with better RFS (P=0.033) and OS (P=0.014). IS was an independent prognostic factor for better OS in multivariate analysis. PD-L1 expression was closely related to tumor vascular invasion (P=0.044). Although there was no association between PD-L1 expression and IS, high PD-L1 expression in tumor cells indicated poor RFS (P=0.017) and OS (P=0.004) in ICC. Conclusion The IS and PD-L1 may be used as a complement to the TNM system for predicting the prognosis of patients with ICC.
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Affiliation(s)
- Hong Wu
- Department of Ultrasound, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Yulong Wei
- Department of Pathology, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Mei Jian
- Department of Ultrasound, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Hong Lu
- Department of Pathology, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Qingzhu Song
- Department of Clinical Laboratory, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Liheng Hao
- Department of Hepatobiliary Surgery, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
| | - Yong Yue
- Department of Hepatobiliary Surgery, Inner Mongolia Bayannaoer City Hospital, Bayannaoer 015000, Inner Mongolia, People's Republic of China
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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Malenica I, Donadon M, Lleo A. Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine. Cancers (Basel) 2020; 12:2190. [PMID: 32781527 PMCID: PMC7464597 DOI: 10.3390/cancers12082190] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/02/2020] [Accepted: 08/03/2020] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3-5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune "hot" and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.
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Affiliation(s)
- Ines Malenica
- Hepatobiliary Immunopathology Unit, Humanitas Clinical and Research Center-IRCCS, 20090 Pieve Emanuele, Italy;
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy;
- Department of Biomedical Science, Humanitas University, 20089 Rozzano, Italy
| | - Ana Lleo
- Department of Biomedical Science, Humanitas University, 20089 Rozzano, Italy
- Internal Medicine and Hepatology Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy
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