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; Eric Jonasch

doi:10.1038/s41467-020-15959-6

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

Nat Commun. 2020 May 1;11(1):2135. doi: 10.1038/s41467-020-15959-6.

Authors

Xian-De Liu^#¹, Wen Kong^#^{2

3}, Christine B Peterson⁴, Daniel J McGrail⁵, Anh Hoang², Xuesong Zhang², Truong Lam², Patrick G Pilie², Haifeng Zhu⁶, Kathryn E Beckermann⁷, Scott M Haake⁷, Sevinj Isgandrova⁸, Margarita Martinez-Moczygemba⁸, Nidhi Sahni⁹, Nizar M Tannir², Shiaw-Yih Lin⁵, W Kimryn Rathmell¹⁰, Eric Jonasch¹¹

Affiliations

¹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].
² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
³ Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200127.
⁴ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁵ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁷ Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁸ Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA.
⁹ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA.
¹⁰ Vanderbilt-Ingram Cancer Center, Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹¹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antigen-Antibody Complex / genetics
Antigen-Antibody Complex / metabolism
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / metabolism*
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Female
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic / genetics
Humans
Immunohistochemistry
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / genetics
Kidney Neoplasms / microbiology*
Mice
Mice, Inbred BALB C
Mice, Knockout
Mutation
Phosphorylation
STAT1 Transcription Factor / metabolism
Tissue Array Analysis
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptome / genetics

Substances

Antigen-Antibody Complex
DNA-Binding Proteins
Pbrm1 protein, mouse
STAT1 Transcription Factor
Stat1 protein, mouse
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding