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.
Nature communications. 2020 May 01*** epublish ***
Xian-De Liu, Wen Kong, Christine B Peterson, Daniel J McGrail, Anh Hoang, Xuesong Zhang, Truong Lam, Patrick G Pilie, 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
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA., Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA., Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. .