CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=35818927
Immunotherapy against cancer is a promising treatment approach, but resistance is a problem. It has been shown that the expression of certain chromatin remodeling factors – that alter chromatin structure to affect gene expression – are associated with immunotherapy resistance in human cancer. Inactivating these factors increases sensitivity to treatment, perhaps by altering the expression of genes that influence response to treatment. This is an avenue of research that has clinical implications. Abstract:
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-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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