Identification of essential genes for cancer immunotherapy

Shashank J. Patel (), Neville E. Sanjana (), Rigel J. Kishton, Arash Eidizadeh, Suman K. Vodnala, Maggie Cam, Jared J. Gartner, Li Jia, Seth M. Steinberg, Tori N. Yamamoto, Anand S. Merchant, Gautam U. Mehta, Anna Chichura, Ophir Shalem, Eric Tran, Robert Eil, Madhusudhanan Sukumar, Eva Perez Guijarro, Chi-Ping Day, Paul Robbins, Steve Feldman, Glenn Merlino, Feng Zhang and Nicholas P. Restifo ()
Additional contact information
Shashank J. Patel: National Cancer Institute, National Institutes of Health (NIH)
Neville E. Sanjana: New York Genome Center
Rigel J. Kishton: National Cancer Institute, National Institutes of Health (NIH)
Arash Eidizadeh: National Cancer Institute, National Institutes of Health (NIH)
Suman K. Vodnala: National Cancer Institute, National Institutes of Health (NIH)
Maggie Cam: National Cancer Institute, National Institutes of Health (NIH)
Jared J. Gartner: National Cancer Institute, National Institutes of Health (NIH)
Li Jia: National Cancer Institute, National Institutes of Health (NIH)
Seth M. Steinberg: National Cancer Institute, National Institutes of Health (NIH)
Tori N. Yamamoto: National Cancer Institute, National Institutes of Health (NIH)
Anand S. Merchant: National Cancer Institute, National Institutes of Health (NIH)
Gautam U. Mehta: National Cancer Institute, National Institutes of Health (NIH)
Anna Chichura: National Cancer Institute, National Institutes of Health (NIH)
Ophir Shalem: University of Pennsylvania
Eric Tran: National Cancer Institute, National Institutes of Health (NIH)
Robert Eil: National Cancer Institute, National Institutes of Health (NIH)
Madhusudhanan Sukumar: National Cancer Institute, National Institutes of Health (NIH)
Eva Perez Guijarro: National Cancer Institute, National Institutes of Health (NIH)
Chi-Ping Day: National Cancer Institute, National Institutes of Health (NIH)
Paul Robbins: National Cancer Institute, National Institutes of Health (NIH)
Steve Feldman: National Cancer Institute, National Institutes of Health (NIH)
Glenn Merlino: National Cancer Institute, National Institutes of Health (NIH)
Feng Zhang: Broad Institute of MIT and Harvard
Nicholas P. Restifo: National Cancer Institute, National Institutes of Health (NIH)

Nature, 2017, vol. 548, issue 7669, 537-542

Abstract: Abstract Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8+ T cells with the resistance or non-responsiveness of cancer to immunotherapies.

Date: 2017
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DOI: 10.1038/nature23477

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