GSE107670
A Major Chromatin Regulator Determines Resistance of Tumor Cells to T cell Mediated Killing
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 anti-tumor immunity.  Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma, resulting in enhanced secretion of chemokines that recruit effector T cells.  Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated.  In many human cancers, expression of PBRM1 and ARID2  inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas  were more strongly infiltrated by cytotoxic T cells. Overall design: Contro, Arid2, Brd7 and Pbrm1 deficient B16F10 cells were either left untreated or treated with IFNg for 24 hours.