Identification of essential genes for cancer immunotherapy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-08-07

AUTHORS

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, Nicholas P. Restifo

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. More... »

PAGES

537-542

References to SciGraph publications

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  • Journal

    TITLE

    Nature

    ISSUE

    7669

    VOLUME

    548

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature23477

    DOI

    http://dx.doi.org/10.1038/nature23477

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1091081816

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28783722


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