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Genomic correlates of response to immune checkpoint blockade

Nature Medicine volume 25, pages 389–402 (2019)Cite this article

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Abstract

Despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Understanding genomic correlates of response and resistance to checkpoint blockade may enhance benefits for patients with cancer by elucidating biomarkers for patient stratification and resistance mechanisms for therapeutic targeting. Here we review emerging genomic markers of checkpoint blockade response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways. Compelling evidence also points to a role for T cell functionality, checkpoint regulators, chromatin modifiers, and copy-number alterations in mediating selective response to immune checkpoint blockade. Ultimately, efforts to contextualize genomic correlates of response into the larger understanding of tumor immune biology will build a foundation for the development of novel biomarkers and therapies to overcome resistance to checkpoint blockade.

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Fig. 1: Framework for genomic correlates of response to immune checkpoint blockade within the tumor immune microenvironment.

Debbie Maizels/Springer Nature

Fig. 2: Antigen presentation and genomic correlates of response to immune checkpoint blockade.

Debbie Maizels/Springer Nature

Fig. 3: Trial designs to overcome checkpoint blockade resistance.

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Acknowledgements

This work was supported by BroadIgnite (E.M.V.A.), BroadNext10 (E.M.V.A., D.M.), NIH R01CA227388 (E.M.V.A.), NIH K08CA188615 (E.M.V.A.), and NIH U01CA233100 (E.M.V.A). This work was also supported by the Center for Immuno-Oncology at the Dana- Farber Cancer Institute and a Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15). Stand Up To Cancer (SU2C) is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C.

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  1. These authors contributed equally: Tanya E. Keenan and Kelly P. Burke

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  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Tanya E. Keenan, Kelly P. Burke & Eliezer M. Van Allen

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Tanya E. Keenan & Eliezer M. Van Allen

  3. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Kelly P. Burke

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T.E.K. and K.P.B. declare no competing interests. E.M.V.A. holds consulting roles with Tango Therapeutics, Invitae, Genome Medical, Illumina, Foresite Capital, and Dynamo, receives research support from Bristol-Myers Squibb and Novartis, owns equity in Tango Therapeutics, Genome Medical, Syapse, and Microsoft, received travel reimbursement from Roche/Genentech, and is on an institutional patent for chromatin mutations and immunotherapy response.

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Keenan, T.E., Burke, K.P. & Van Allen, E.M. Genomic correlates of response to immune checkpoint blockade. Nat Med 25, 389–402 (2019). https://doi.org/10.1038/s41591-019-0382-x

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