Review Article | Published:

Cancer immunoediting and resistance to T cell-based immunotherapy

Nature Reviews Clinical Oncologyvolume 16pages151167 (2019) | Download Citation

Abstract

Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance.

Key points

  • Cancer immunoediting proceeds through three phases: elimination, equilibrium and escape.

  • Cancer immunoediting occurs during tumour progression but also in patients receiving anticancer immunotherapies.

  • Innate and acquired resistance to immunotherapy are important barriers to treatment effectiveness.

  • The availability of large amounts of new information on the genomic and transcriptomic profile of various human malignancies adds extra depth to our ability to stratify the tumour microenvironment.

  • Tumours can be stratified on the basis of their mutational burden and the presence or absence of a T cell-inflamed gene signature.

  • Immunotherapies should be considered as a therapeutic option in patients who have pre-malignant or dormant tumours that might eventually progress or relapse.

  • The optimal approaches to achieve tumour elimination will involve therapeutic combinations to promote immune activation and T cell priming, suppress immunosuppressive signals in the tumour microenvironment and sustain the presence of T cells within the tumour tissue.

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Acknowledgements

The work of J.S.O’D. has been supported by an Australian Postgraduate Award and a QIMR Berghofer PhD Top-Up Scholarship. The research of M.W.L.T. is supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (1098960). The research of M.J.S. is funded by an NHMRC Senior Principal Research Fellowship (1078671) and an NHMRC Program Grant (1132519).

Reviewer information

Nature Reviews Clinical Oncology thanks S. Ferrone, M. Manjili and the other anonymous peer reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: Michele W. L. Teng, Mark J. Smyth

Affiliations

  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Queensland, Australia

    • Jake S. O’Donnell
    •  & Mark J. Smyth
  2. Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Queensland, Australia

    • Jake S. O’Donnell
    •  & Michele W. L. Teng
  3. School of Medicine, The University of Queensland, Queensland, Australia

    • Jake S. O’Donnell
    • , Michele W. L. Teng
    •  & Mark J. Smyth

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Contributions

All authors made substantial contributions to each stage of the preparation of this manuscript for publication.

Competing interests

M.W.L.T. has received honoraria from Arcus Biosciences, Boehringer Ingelheim, Bristol-Myers Squib and Merck Sharp and Dohme. The work of M.J.S. is funded by research agreements from Aduro Biotech, Bristol-Myers Squib and Tizona Therapeutics. J.S.O’D. declares no competing interests.

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Correspondence to Michele W. L. Teng or Mark J. Smyth.

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