PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2020
- Source ID
- 10.1038/s41467-020-15959-6
Entities
People
- Anh Hoang
- Christine B Peterson
- Daniel J. Mcgrail
- Eric Jonasch
- Haifeng Zhu
- Kathryn E. Beckermann
- Margarita Martinez-moczygemba
- Nidhi Sahni
- Nizar M. Tannir
- Patrick G. Pilie
- Scott M. Haake
- Sevinj Isgandrova
- Shiaw-Yih Lin
- Truong Lam
- W. Kimryn Rathmell
- Wen Kong
- Xian-De Liu
- Xuesong Zhang
Organizations
- National Cancer Institute
- United States Department of Defense