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 antitumor immunity. Inactivation of >100 genes-including <i>Pbrm1</i>, <i>Arid2</i>, and <i>Brd7</i>, 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 <i>Pbrm1</i> was inactivated. In many human cancers, expression of <i>PBRM1</i> and <i>ARID2</i> inversely correlated with expression of T cell cytotoxicity genes, and <i>Pbrm1</i>-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.