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Ref Type Journal Article
PMID (29301958)
Authors Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay RE, Luoma AM, Tsoucas D, Qiu X, Lim K, Rao P, Long HW, Yuan GC, Doench J, Brown M, Liu XS, Wucherpfennig KW
Title A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.
Journal Science (New York, N.Y.)
Vol 359
Issue 6377
Date 2018 02 16
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PBRM1 loss melanoma sensitive unspecified CTLA4 antibody + unspecified PD-1 antibody Preclinical - Cell line xenograft Actionable In a preclinical study, knocking-out PBRM1 in melanoma cells sensitized cells to immune therapy consisted of anti-CTLA4 and anti-PD-1 antibodies in culture and in cell line xenograft models, potentially due to increased sensitivity to T cell-mediated cytotoxicity and a favorable tumor microenvironment (PMID: 29301958). 29301958