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

XD Liu, W Kong, CB Peterson, DJ McGrail… - Nature …, 2020 - nature.com
XD Liu, W Kong, CB Peterson, DJ McGrail, A Hoang, X Zhang, T Lam, PG Pilie, H Zhu…
Nature communications, 2020nature.com
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 …
Abstract
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.
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