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  • Review Article
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Immunology and immunotherapy of cholangiocarcinoma

Nature Reviews Gastroenterology & Hepatology volume 20, pages 349–365 (2023)Cite this article

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Abstract

Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.

Key points

  • Biliary tumours are surrounded by a desmoplastic tumour microenvironment dominated by cancer-associated fibroblasts and myeloid and macrophage cell populations with immunosuppressive function.

  • Different molecular subtypes based on immune profiles have been described for patients with cholangiocarcinoma and might be usable for patient stratification.

  • The advent of mouse cholangiocarcinoma models in immunocompetent mice allows the development and testing of novel immune-based treatment options for cholangiocarcinoma.

  • Combined chemotherapy with immunotherapy has become the standard-of-care systemic frontline treatment option for patients with cholangiocarcinoma.

  • Various immune-based therapies are currently being tested in patients with cholangiocarcinoma.

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Fig. 1: The immune tumour microenvironment in cholangiocarcinoma.
Fig. 2: Cancer-associated fibroblast subtypes and interacting cells in cholangiocarcinoma.
Fig. 3: Cancer immunotherapy in cholangiocarcinoma.

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Acknowledgements

T.F.G., L.M. and X.W.W. are supported by the NIH Intramural Research Program (grants ZIA BC 011345 and ZIA BC 010313). R.S. is supported by grant NIH R01CA228483 and the Columbia University Digestive and Liver Disease Research Center grant 1P30DK132710-01. L.G. receives funding from the American Cancer Society (Clinical Scientist Development Grant 134013‐CSDG‐19‐163‐01‐TBG) and the NIH/NCI Gastrointestinal Cancer grant SPORE P50 CA127003.

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Authors and Affiliations

  1. Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Tim F. Greten

  2. Liver Cancer Program, Bethesda, MD, USA

    Tim F. Greten & Xin W. Wang

  3. Institute of Human Nutrition, Columbia University, New York, NY, USA

    Robert Schwabe

  4. Department of Medicine, Columbia University, New York, NY, USA

    Robert Schwabe

  5. Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Nabeel Bardeesy

  6. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Nabeel Bardeesy

  7. Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Lichun Ma

  8. Division of Oncology, Stanford School of Medicine, Palo Alto, CA, USA

    Lipika Goyal

  9. Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    Robin K. Kelley

  10. Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Xin W. Wang

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Contributions

R.S., N.B., L.M., L.G., R.K.K. and X.W.W. researched data for the article. R.S., N.B., L.M., L.G., R.K.K. and X.W.W. contributed substantially to discussion of the content. All authors wrote the article. R.S., N.B., L.M., L.G., R.K.K. and X.W.W. reviewed and/or edited the manuscript before submission.

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Correspondence to Tim F. Greten.

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Competing interests

R.K.K. has received research funding (to institution) from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology and Taiho Oncology. R.K.K. has received payments for consulting or advisory board membership (to institution) from Agios, AstraZeneca, Exelixis, Ipsen, Merck and (to self) from Exact Sciences and Kinnate. L.G. has received research funding (to institution) from Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED, Servier, Taiho Oncology, Leap Therapeutics, Bristol Myers Squibb and Nucana; and serves as an adviser/consultant to Alentis Therapeutics, AstraZeneca, Black Diamond, Exelixis, Genentech, H3Biomedicine, Incyte Corporation, Kinnate, QED Therapeutics, Servier, Sirtex Medical Ltd, TranstheraBio and Taiho Oncology Inc. N.B. receives research funding from Kinnate Biopharma, Taiho Oncology, Relay, Bristol Myers Squibb and Servier Laboratories. T.F.G. receives research funding (to institution) from Merck and AstraZeneca. R.S., X.W.W. and L.M. declare no competing interests.

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scAtlasLC: https://scatlaslc.ccr.cancer.gov/

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Greten, T.F., Schwabe, R., Bardeesy, N. et al. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 20, 349–365 (2023). https://doi.org/10.1038/s41575-022-00741-4

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