A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing

• Published in: Science (American Association for the Advancement of Science) Vol. 359; no. 6377; pp. 770 - 775
• Main Authors: Pan, Deng, Kobayashi, Aya, Jiang, Peng, Ferrari de Andrade, Lucas, Tay, Rong En, Luoma, Adrienne M, Tsoucas, Daphne, Qiu, Xintao, Lim, Klothilda, Rao, Prakash, Long, Henry W, Yuan, Guo-Cheng, Doench, John, Brown, Myles, Liu, X Shirley, Wucherpfennig, Kai W
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 16-02-2018
• Subjects: Animals; Antitumor activity; Bacterial Proteins; Cell Line, Tumor; Chemokines; Chromatin remodeling; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; CRISPR; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Cytokines; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Deactivation; DNA-Binding Proteins; Drugs; Effector cells; Endonucleases; Gene expression; Genes; Genetic Testing; Genomes; HMGB Proteins - genetics; HMGB Proteins - metabolism; Humans; Immune checkpoint inhibitors; Immunity; Immunosuppressive agents; Immunotherapy; Inactivation; Inhibitors; Interferon; Interferon-gamma - therapeutic use; Kidney cancer; Lymphocytes; Lymphocytes T; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Mice; Mutation; Narcotics; Patients; Renal cell carcinoma; Sensitivity; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - therapy; SWI/SNF complex; T-Lymphocytes, Cytotoxic - immunology; Toxicity; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cells; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao1710

Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including
,
, and
, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when
was inactivated. In many human cancers, expression of
and
inversely correlated with expression of T cell cytotoxicity genes, and
-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.