Patel et al. employed a “two cell type” CRISPR screen to identify genes expressed in cancer cells that facilitate the effector functions of T cells and thus may promote immune escape by tumors. Both known (HLA-A, B2M) and novel (CD58, APLNR) genes involved in antigen presentation and IFN-γ signaling pathways, among others, were identified and validated.
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-gamma 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-gamma 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.
Author Info: (1) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. NIH-Georgetown University Graduate Partnership Program, Georgetown University Med
Author Info: (1) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. NIH-Georgetown University Graduate Partnership Program, Georgetown University Medical School, Washington DC 20057, USA. (2) New York Genome Center, New York, New York 10013, USA. Department of Biology, New York University, New York, New York 10012, USA. (3) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (4) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (5) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (6) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (7) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (8) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (9) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (10) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. (11) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (12) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (13) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (14) Children's Hospital of Philadelphia and Department of Genetics, University of Pennsylvania, Pennsylvania 19104, USA. (15) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (16) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (17) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (18) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (19) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (20) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (21) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (22) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. (23) Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. (24) National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
