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. 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 and Eric Jonasch ()
Additional contact information
Xian- De Liu: The University of Texas MD Anderson Cancer Center
Wen Kong: The University of Texas MD Anderson Cancer Center
Christine B. Peterson: The University of Texas MD Anderson Cancer Center
Daniel J. McGrail: The University of Texas MD Anderson Cancer Center
Anh Hoang: The University of Texas MD Anderson Cancer Center
Xuesong Zhang: The University of Texas MD Anderson Cancer Center
Truong Lam: The University of Texas MD Anderson Cancer Center
Patrick G. Pilie: The University of Texas MD Anderson Cancer Center
Haifeng Zhu: The University of Texas MD Anderson Cancer Center
Kathryn E. Beckermann: Vanderbilt University Medical Center
Scott M. Haake: Vanderbilt University Medical Center
Sevinj Isgandrova: Institute of Biosciences and Technology, Texas A&M Health Science Center
Margarita Martinez-Moczygemba: Institute of Biosciences and Technology, Texas A&M Health Science Center
Nidhi Sahni: The University of Texas MD Anderson Cancer Center
Nizar M. Tannir: The University of Texas MD Anderson Cancer Center
Shiaw-Yih Lin: The University of Texas MD Anderson Cancer Center
W. Kimryn Rathmell: Vanderbilt University Medical Center
Eric Jonasch: The University of Texas MD Anderson Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15959-6

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