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  • Review Article
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Biomarkers for immunotherapy of hepatocellular carcinoma

Nature Reviews Clinical Oncology volume 20, pages 780–798 (2023)Cite this article

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Abstract

Immune-checkpoint inhibitors (ICIs) are now widely used for the treatment of patients with advanced-stage hepatocellular carcinoma (HCC). Two different ICI-containing regimens, atezolizumab plus bevacizumab and tremelimumab plus durvalumab, are now approved standard-of-care first-line therapies in this setting. However, and despite substantial improvements in survival outcomes relative to sorafenib, most patients with advanced-stage HCC do not derive durable benefit from these regimens. Advances in genome sequencing including the use of single-cell RNA sequencing (both of tumour material and blood samples), as well as immune cell identification strategies and other techniques such as radiomics and analysis of the microbiota, have created considerable potential for the identification of novel predictive biomarkers enabling the accurate selection of patients who are most likely to derive benefit from ICIs. In this Review, we summarize data on the immunology of HCC and the outcomes in patients receiving ICIs for the treatment of this disease. We then provide an overview of current biomarker use and developments in the past 5 years, including gene signatures, circulating tumour cells, high-dimensional flow cytometry, single-cell RNA sequencing as well as approaches involving the microbiome, radiomics and clinical markers. Novel concepts for further biomarker development in HCC are then discussed including biomarker-driven trials, spatial transcriptomics and integrated ‘big data’ analysis approaches. These concepts all have the potential to better identify patients who are most likely to benefit from ICIs and to promote the development of new treatment approaches.

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Fig. 1: Materials needed for rigorous biomarker investigations.
Fig. 2: Overview of the sources of various biomarker candidates for immunotherapy of HCC.
Fig. 3: Trial design for biomarker identification studies.
Fig. 4: Trial designs for biomarker-driven clinical trials.

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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, Firouzeh Korangy & Benjamin Ruf

  2. Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Tim F. Greten & Xin W. Wang

  3. Divisions of Liver Disease and Hematology/Medical Oncology, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Augusto Villanueva

  4. Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark Yarchoan

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

    Lichun Ma & Eytan Ruppin

  6. 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

A.V., F.K., M.Y., L.M., E.R. and X.W.W researched data for the manuscript and made a substantial contribution to discussions of content. All authors wrote the manuscript, and A.V., F.K., B.R. M.Y., L.M. and E.R. edited and/or reviewed the manuscript prior to submission.

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Correspondence to Tim F. Greten.

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Competing interests

A.V. has acted as a consultant and/or adviser for Astra Zeneca, BMS, Eisai, FirstWorld, Genentech, Natera, NGM Pharmaceuticals, Pioneering Medicine and Roche; has received research support from Eisai; has stock options from Espervita; and is listed as an inventor on a patent related to early detection of HCC (PCT/US20/61441). M.Y. has acted as a consultant and/or adviser for AstraZeneca, Eisai, Exelixis, Genentech, Hepion and Replimune; has received research funding from Bristol-Myers Squibb, Genentech and Incyte; and holds equity in Adventris Pharmaceuticals. The other authors declare no competing interests.

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Greten, T.F., Villanueva, A., Korangy, F. et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol 20, 780–798 (2023). https://doi.org/10.1038/s41571-023-00816-4

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