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- Title
PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma.
- Authors
Liu, Xian-De; Kong, Wen; Peterson, Christine B.; McGrail, Daniel J.; Hoang, Anh; Zhang, Xuesong; Lam, Truong; Pilie, Patrick G.; Zhu, Haifeng; Beckermann, Kathryn E.; Haake, Scott M.; Isgandrova, Sevinj; Martinez-Moczygemba, Margarita; Sahni, Nidhi; Tannir, Nizar M.; Lin, Shiaw-Yih; Rathmell, W. Kimryn; Jonasch, Eric
- 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. PBRM1, encoding for a subunit of the SWI/SNF complex, is the second most frequently mutated gene in clear cell renal cell carcinoma (ccRCC). Here, the authors show that PBRM1 loss reduces IFNγ-mediated signalling resulting in a less immunogenic tumor microenvironment and that PBRM1 mutations correlate with lack of response to checkpoint inhibitor therapy in ccRCC patients..
- Subjects
BRAF genes; RENAL cell carcinoma; ANIMAL models in research; TUMOR microenvironment; CARCINOMA; PHENOTYPES; PROGRAMMED cell death 1 receptors
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-15959-6