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Tumour-intrinsic resistance to immune checkpoint blockade

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Abstract

‘Immune checkpoint blockade’ for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT–β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.

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Fig. 1: Interferon signalling in adaptive programmed cell death 1 ligand 1 expression.
Fig. 2: Timeline of original discoveries of the importance of the interferon-γ (IFNγ) pathway and antigen presentation in antitumour immunity.
Fig. 3: Resistance to immune checkpoint blockade: tumour-intrinsic escape mechanisms.
Fig. 4: Overcoming tumour-intrinsic resistance to immune checkpoint blockade.
Fig. 5: Oncogenic signalling pathways affecting antitumour immunity and resistance to immune checkpoint blockade.

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Acknowledgements

The authors are supported by grants from the Parker Institute for Cancer Immunotherapy (A.R.), the US National Institutes of Health (grant R35 CA197633 to A.R.), the University of California, Los Angeles (CTSI KL2 Award to A.K.), the Sarcoma Alliance for Research Through Collaboration Career Enhancement Program (A.K.) and the Ressler Family Fund (A.R.).

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Nature Reviews Immunology thanks R. Jenkins and S. Subramanian, and other, anonymous, reviewer(s), for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Anusha Kalbasi.

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A.K. has no competing financial or other conflicts of interest. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis and Roche and is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix and Tango Therapeutics.

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Glossary

BRAF-V600E

A specific activating mutation in the BRAF gene commonly found in human melanoma, which results in increased cell growth.

Synthetic ‘AND-gate’ logic switches

Type of chimeric antigen receptor constructs that use synthetic Notch receptors. Sensing of ligand by the synthetic Notch receptor induces transcription of a chimeric antigen receptor that is specific for a second ligand. T cell activation is achieved only when both ligands are present.

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Kalbasi, A., Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol 20, 25–39 (2020). https://doi.org/10.1038/s41577-019-0218-4

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