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Combinatorial targeting of immune checkpoints and epigenetic regulators for hepatocellular carcinoma therapy

Oncogene volume 42, pages 1051–1057 (2023)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The five-year survival rate of patients with unresectable HCC is about 12%. The liver tumor microenvironment (TME) is immune tolerant and heavily infiltrated with immunosuppressive cells. Immune checkpoint inhibitors (ICIs), in some cases, can reverse tumor cell immune evasion and enhance antitumor immunity. Rapidly evolving ICIs have expanded systemic treatment options in advanced HCC; however, single-agent ICIs achieve a limited 15–20% objective response rate in advanced HCC. Therefore, other combinatorial approaches that amplify the efficacy of ICIs or suppress other tumor-promoting pathways may enhance clinical outcomes. Epigenetic alterations (e.g., changes in chromatin states and non-genetic DNA modifications) have been shown to drive HCC tumor growth and progression as well as their response to ICIs. Recent studies have combined ICIs and epigenetic inhibitors in preclinical and clinical settings to contain several cancers, including HCC. In this review, we outline current ICI treatments for HCC, the mechanism behind their successes and failures, and how ICIs can be combined with distinct epigenetic inhibitors to increase the durability of ICIs and potentially treat “immune-cold” HCC.

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Fig. 1: Epigenetic immune modulation of HCC and ICI in combination with epigenetic regulators for improved therapeutic outcomes.

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Data availability

All the data is available under reasonable request. Materials requests should be addressed to nwajapey@uab.edu.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center of University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, 35233, USA

    Mehmet Akce & Bassel F El-Rayes

  2. Department of Biochemistry and Molecular Genetics, O’Neal Comprehensive Cancer Center of University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL, 35233, USA

    Narendra Wajapeyee

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MA and NW led the writing and co-wrote this review. BE provided input and suggestions on the relevant clinical sections.

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Correspondence to Mehmet Akce or Narendra Wajapeyee.

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Dr. Mehmet Akce has received research support from Tesaro, RedHill Biopharma, Polaris, Bristol-Myers-Squibb-Ono Pharmaceutical, Xencor, Merck Sharp& Dohme, Eisai, GSK, and AstraZeneca. Dr. Mehmet Akce has also served as a consultant for Eisai, Ipsen, Exelixis, GSK, QED, Isofol, Curio Science, AstraZeneca, Genentech. Dr. Bassel El-Rayes has received research support from EUSA, Novartis, BMS, Exelixis, Xencor, Merck, Adaptimmune. Dr. Bassel El-Rayes has also served as a consultant for IPSEN, BMS, AstraZeneca, deciphera, neogenomics, DSMB, Exelixis, and Erytech. Dr. Narendra Wajapeyee has no conflict of interest to declare.

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Akce, M., El-Rayes, B.F. & Wajapeyee, N. Combinatorial targeting of immune checkpoints and epigenetic regulators for hepatocellular carcinoma therapy. Oncogene 42, 1051–1057 (2023). https://doi.org/10.1038/s41388-023-02646-1

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