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

Author

Listed:
  • Xian-De Liu

    (The University of Texas MD Anderson Cancer Center)

  • Wen Kong

    (The University of Texas MD Anderson Cancer Center
    Shanghai Jiao Tong University School of Medicine)

  • 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)

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.

Suggested Citation

  • 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 Isgandrov, 2020. "PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15959-6
    DOI: 10.1038/s41467-020-15959-6
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    Cited by:

    1. Akihiko Fukagawa & Natsuko Hama & Yasushi Totoki & Hiromi Nakamura & Yasuhito Arai & Mihoko Saito-Adachi & Akiko Maeshima & Yoshiyuki Matsui & Shinichi Yachida & Tetsuo Ushiku & Tatsuhiro Shibata, 2023. "Genomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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