PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma
Xian-De Liu, Wen Kong, Christine B. Peterson, Daniel J. McGrail, Anh Hoang, Xuesong Zhang, Truong Lam, Patrick G. Pilié, Haifeng Zhu, Kathryn E. Beckermann, Scott M. Haake, Sevinj Isgandrova, Margarita Martinez-Moczygemba, Nidhi Sahni, Nizar M. Tannir, Shiaw‐Yih Lin, W. Kimryn Rathmell, Eric Jonasch
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.