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

D Pan, A Kobayashi, P Jiang, L Ferrari de Andrade… - Science, 2018 - science.org
D Pan, A Kobayashi, P Jiang, L Ferrari de Andrade, RE Tay, AM Luoma, D Tsoucas, X Qiu
Science, 2018science.org
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 Pbrm1, Arid2, and Brd7, 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 …
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 Pbrm1, Arid2, and Brd7, 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 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.
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