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

• DOI: 10.1038/s41467-020-15959-6
• Publication Date: 2020-05-01T10:02:39Z
• Authors: Xian-De Liu; Wen Kong; Christine B. Pete...; Daniel J. McGrail; Anh Hoang; Xuesong Zhang; Truong Lam; Patrick G. Pilie; Haifeng Zhu; Kathryn E. Becker...; Scott M. Haake; Sevinj Isgandrova; Margarita Martine...; Nidhi Sahni; Nizar M. Tannir; Shiaw-Yih Lin; W. Kimryn Rathmell; Eric Jonasch
• Keywords: 0301 basic medicine; Science; Fluorescent Antibody Technique; Antigen-Antibody Complex; Article; Mice; 03 medical and health sciences; Animals; Humans; Phosphorylation; Carcinoma, Renal Cell; Mice, Knockout; Mice, Inbred BALB C; Q; Immunohistochemistry; Kidney Neoplasms; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; STAT1 Transcription Factor; Tissue Array Analysis; Mutation; Female; Transcriptome; Transcription Factors

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