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.
Highlights
A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response
Though we found a consistently decreased immunogenic TME in Clear cell renal cell carcinoma (ccRCC) patients with PBRM1 loss across 5 patient cohorts, a previous Cas9-based screen in murine melanoma cells indicated that loss of PBRM1 may increase tumor immunogenicity[24]
We employed an isogenic murine renal cell carcinoma (RCC) model to investigate the impact of PBRM1 loss on tumor-autonomous IFNγ signaling and on the TME, measured the effect of PBRM1 loss on response to ICB, and validated our findings in human ccRCC datasets
Summary
A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. ICB response in melanoma has revealed that a non-immunogenic tumor microenvironment (TME) is a significant barrier to immunotherapy benefit[6,7]. Response to ICB requires the presence of antitumor T cells in the TME, while their activity is inhibited by checkpoint pathways[8,9] This subset of responsive tumors is associated with an immunogenic TME as characterized by the high expression of T cell-inflamed signatures or of IFNγ-related profiles[10,11]. Defects in the IFNγ signaling pathway, mutations in IFNGR1, JAK1, JAK2, and STAT1, induced resistance to ICB in patients with metastatic melanoma[12,13,14]. It is conceivable that, in patients with ccRCC, the interaction between fundamental gene mutations in tumor cells and the TME determines resistance to immunotherapy
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