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