n425423SE Academic Article uri icon

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 IFN receptor 2 (Ifngr2) promoter, decreasingSTAT1 phosphorylation and the subsequent expression of IFN 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 IFN-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.

published proceedings

  • Nat Commun

author list (cited authors)

  • Liu, X., Kong, W., Peterson, C. B., McGrail, D. J., Hoang, A., Zhang, X., ... Jonasch, E.

publication date

  • January 1, 2020 11:11 AM