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Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities

Nature Reviews Drug Discovery volume 21, pages 529–540 (2022)Cite this article

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Abstract

Tumours employ various tactics to adapt and eventually resist immune attack. These mechanisms are collectively called adaptive immune resistance (AIR). The first defined and therapeutically validated AIR mechanism is the selective induction of programmed cell death 1 ligand 1 (PDL1) by interferon-γ in the tumour. Blockade of PDL1 binding to its receptor PD1 by antibodies (anti-PD therapy) has resulted in remission of a fraction of patients with advanced-stage cancer, especially in solid tumours. However, many clinical trials combining anti-PD therapy with other antitumour drugs conducted without a strong mechanistic rationale have failed to identify a synergistic or additive effect. In this Perspective article, we discuss why defining AIR mechanisms at the tumour site should be a key focus to direct future drug development as well as practical approaches to improve current cancer therapy.

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Fig. 1: Resistance to anti-PD therapy depending on type of tumour immune microenvironment.

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Acknowledgements

T.K.K. is a recipient of American Cancer Society Clinician Scientist Development Grant 2019, American Society of Hematology Scholar Award 2016, American Society of Clinical Oncology Career Development Grant 2018, the Edward P. Evans Foundation Young Investigator Award 2018.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Tae Kon Kim

  2. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA

    Tae Kon Kim, Roy S. Herbst & Lieping Chen

  3. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Esten N. Vandsemb

  4. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Lieping Chen

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Correspondence to Lieping Chen.

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R.S.H. is a consultant for AstraZeneca, Merck, Genentech/Roche, Lilly, Bristol-Myers Squibb, and a scientific adviser of NextCure. L.C. is a scientific founder, consultant and/or board member of NextCure, Junshi, Tayu, Normunity, Zai Lab, Tpioneer, Vcanbio and GenomiCare; and has sponsored research funds from NextCure, Normunity and DynamiCure. The other authors declare no competing interests.

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Kim, T.K., Vandsemb, E.N., Herbst, R.S. et al. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov 21, 529–540 (2022). https://doi.org/10.1038/s41573-022-00493-5

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