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A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of  Polybromo-1  ( PBRM1 ) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that  PBRM1 / Pbrm1  deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 ( Ifngr2 ) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis.  Pbrm1  deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that  PBRM1  mutation reduces benefit from ICB. Our study sheds light on the influence of  PBRM1  mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.

PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma