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Immunological landscape and immunotherapy of hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 12, pages 681–700 (2015)Cite this article

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This article has been updated

Key Points

  • Hepatocellular carcinoma (HCC) is an immunogenic liver lesion that expresses shared tumour antigens (tumour-associated antigens) and private neo-antigens arising from specific gene mutations

  • Despite HCC antigenicity and intratumour accumulation of effector T cells, antitumour immune responses are subverted by a variety of stromal cells and multiple immunoinhibitory molecules

  • Different immunotherapeutic modalities have been used to treat HCC, including diverse vaccine platforms, adoptive T-cell therapy, cytokines, gene therapy and monoclonal antibodies that target immune checkpoint molecules

  • The abundance of additive immunosuppressive factors in the HCC microenvironment calls for a multitargeted approach, combining systemic and locoregional therapeutic modalities

  • Administration of monoclonal antibodies, adoptive T-cell therapy or vaccines in combination with gene therapy vectors that encode monoclonal antibodies and/or immunostimulatory cytokines are powerful strategies to treat HCC

Abstract

Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.

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Figure 1: Inhibition of DC immunogenic functions by the HCC microenvironment.
Figure 2: Inhibition of NK and T cell effector functions by the HCC microenvironment.
Figure 3: Activation of antitumour responses by the checkpoint-blocking antibody anti-CTLA-4.
Figure 4: Activation of antitumour responses by checkpoint-blocking antibodies against PD-1 or PD-L1.
Figure 5: Classification of immunotherapies.
Figure 6: Combination therapy for HCC.
Figure 7: Clinical options for HCC therapy.

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Change history

  • 03 November 2015

    In the version of this article originally published online an affiliation was missing for Bruno Sangro and has now been added. The error has been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

The authors wish to express deep gratitude to colleagues of the Division of Hepatology and Gene Therapy of the Centre of Applied Medical Research (CIMA) of the University of Navarra, the Liver Unit and the Clinical Trial Unit of the University Clinic of Navarra, Drs J.J. Lasarte, P. Sarobe, M. Avila, F. Corrales, C. Berasain, R. Hernandez-Alcoceba, C. Smerdou, P. Berraondo, R. Aldabe, G. Gonzalez-Aseguinolaza, J. Quiroga, M. Iñarrairaegui, J.I. Herrero, J.L. Perez-Gracia as well as to Dr Ch. Qian (Chongching Military Hospital) for their collaboration, inspiration and input in research and medical assistance during many years as well as the secretary M.E. Perez-Mena for her help in the writing of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Clinica Universidad de Navarra and Centre for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII, 31080, Pamplona, Spain

    Jesús Prieto

  2. Department of Oncology, Clinica Universidad de Navarra and Centre for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII, 31080, Pamplona, Spain

    Ignacio Melero

  3. Liver Unit, Clinica Universidad de Navarra and Centre for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII, 31080, Pamplona, Spain

    Bruno Sangro

  4. CIBERehd, Instituto de Salud Carlos III, Monforte de Lemos 3-5, Avenida Pio XII, 28029, Madrid, Spain

    Bruno Sangro

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J.P. and B.S. contributed equally to researching data for the manuscript, discussion of content and writing. All authors contributed equally to reviewing and editing the manuscript before submission.

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Correspondence to Jesús Prieto.

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Competing interests

B.S. has acted as a consultant to Bristol–Myers Squibb. I.M. has acted as a consultant to AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Genentech, LeadArtis, Miltenyi Biotec, Roche. J.P. declares no competing interests.

Supplementary information

Supplementary Table 1

Immunotherapies with FDA-approval for cancer treatment (DOC 84 kb)

Supplementary Table 2

Clinical trials on cell-based immunotherapies (DCs) in HCC (DOC 84 kb)

Supplementary Table 3

Clinical trials on cell-based immunotherapies (CIKs) in HCC (DOC 84 kb)

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Prieto, J., Melero, I. & Sangro, B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 12, 681–700 (2015). https://doi.org/10.1038/nrgastro.2015.173

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