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  • Review Article
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Cholangiocarcinoma — novel biological insights and therapeutic strategies

Nature Reviews Clinical Oncology volume 20, pages 470–486 (2023)Cite this article

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Abstract

In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of ‘immune-desert’ tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.

Key points

  • Cholangiocarcinomas (CCAs) are highly desmoplastic cancers characterized by a tumour microenvironment that is poorly immunogenic, with an abundance of immunosuppressive cell types such as myeloid-derived suppressor cells and tumour-associated macrophages.

  • The desmoplasia of CCAs is associated with an abundance of heterogeneous cancer-associated fibroblasts (CAFs), with several transcriptomically diverse CAF subtypes identified.

  • Assessments of circulating tumour cells and cell-free tumour DNA are becoming important in the diagnosis and monitoring of CCA.

  • Potent oncogenic drivers of intrahepatic CCAs (iCCAs) include fibroblast growth factor receptor 2 (FGFR2) gene fusions and neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1). FGFR2 fusions and IDH1 mutations are targetable, and approved molecularly targeted therapies are now available for the treatment of CCAs harbouring these genetic aberrations.

  • The results of immune-checkpoint inhibitor monotherapy in patients with CCA have been disappointing, although the combination of gemcitabine, cisplatin and durvalumab has been approved in the first-line setting for the treatment of advanced-stage CCA.

  • Liver transplantation is an emerging option for the subset of patients with early stage iCCA occurring in the setting of cirrhosis.

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Fig. 1: Therapeutically re-engineering the TIME of CCA to reduce tumour burden.
Fig. 2: Different shades of CAF heterogeneity in CCA.

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Acknowledgements

The work of the authors is supported by the US National Institutes of Health (NIH)/National Cancer Institute (NCI) grants SPORE P50 CA210964 (to S.I.I. and G.J.G.) and 1K08CA236874 (to S.I.I.). The work of S.A. is supported by a fellowship from “la Caixa” Foundation (ID 100010434) and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 847648. The work of L.G. is supported by American Cancer Society Clinical Scientist Development Grant 134013‐CSDG‐19‐163‐01‐TBG and NIH/NCI Gastrointestinal Cancer SPORE P50 CA127003. A.L. has received funding from The Christie Charity and the European Union’s Horizon 2020 research and innovation programme (grant no. 82551, ESCALON). J.D.Y. has received an American College of Gastroenterology Junior Faculty Development Award and a U.S. Department of Defense Peer Reviewed Cancer Research Program Career Development Award (CA 191051).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Sumera I. Ilyas & Gregory J. Gores

  2. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    Sumera I. Ilyas

  3. Liver, Digestive System and Metabolism Research, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Silvia Affo

  4. Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA

    Lipika Goyal

  5. Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain

    Angela Lamarca

  6. Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK

    Angela Lamarca

  7. Division of Cancer Sciences, University of Manchester, Manchester, UK

    Angela Lamarca

  8. Ajmera Transplant Program and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Canada

    Gonzalo Sapisochin

  9. Karsh Division of Gastroenterology and Hepatology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Ju Dong Yang

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Contributions

S.I.I., J.D.Y. and G.J.G. contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. All authors contributed to researching data for the article and writing the manuscript.

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Correspondence to Gregory J. Gores.

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Competing interests

S.I.I. serves as an adviser and consultant to AstraZeneca. L.G. has received research funding (via her institution) from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Genentech, Incyte, Leap Therapeutics, Loxo Oncology, Macrogenics, Merck, Novartis, Nucana, QED Therapeutics, Relay Therapeutics, Servier and Taiho Oncology, and serves as an adviser or consultant to Alentis Therapeutics, AstraZeneca, Black Diamond, Exelixis, Genentech, H3Biomedicine, Incyte, QED Therapeutics, Servier, Sirtex Medical, Taiho Oncology and Transthera Bio. A.L. declares travel and educational support from Advanced Accelerator Applications, Bayer, Delcath, Ipsen, Mylan, Novartis, Pfizer and SirtEx; speaker’s honoraria from Advanced Accelerator Applications, AstraZeneca, Eisai, Incyte, Ipsen, Merck, Pfizer, QED Therapeutics and Servier; and advisory or consultancy roles with Albireo Pharma, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Eisai, GENFIT, Ipsen, Nutricia, QED Therapeutics, Roche, Servier and TransThera Biosciences; and is a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. G.S. has received grant support from Roche, and declares consultancy roles with AstraZeneca, Chiesi, Evidera, Integra, Novartis and Roche. S.A., J.D.Y. and G.J.G. declare no competing interests.

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Nature Reviews Clinical Oncology thanks C. Berasain, H. Francis, T. Greten, and J. Harding for their contribution to the peer review of this work.

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Ilyas, S.I., Affo, S., Goyal, L. et al. Cholangiocarcinoma — novel biological insights and therapeutic strategies. Nat Rev Clin Oncol 20, 470–486 (2023). https://doi.org/10.1038/s41571-023-00770-1

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