Abstract 3724: PBRM1 loss in RCC: Implications for immunotherapy

Abstract

Abstract Introduction The association between mutational status of the polybromo-1 (PBRM1) gene in clear cell renal cell carcinomas (ccRCCs) and papillary RCCs (pRCCs) in the response to immune checkpoint blockade is debatable. Here, we aim to characterize the biological changes that PBRM1 loss causes and how these changes might modulate the immune response to cancer. Methods and Results Gene set enrichment analysis (GSEA) of PBRM1-mutant RCC tumors from TCGA data sets reveals NF-kB signaling via TNFα, hypoxia, and p53 signaling pathways are enriched compared to PBRM1 WT. PBRM1-mutant tumors also have increased number of insertion/deletion mutations and non-synonymous mutations that are directly proportional to neoantigen burden. CIBERSORT analysis of PBRM1-mutant ccRCC tumors reveals decreased transcriptional signature associated with CD8+ T-cell infiltration and lower levels of two cytolytic signatures. PBRM1-mutant ccRCC cell lines have constitutively activated NF-kB signaling, as well as a greater induction of NF-kB in response to TNFα via western blot when compared with PBRM1 reconstituted cells. Additionally, PD-L1 is more strongly expressed on the cell surface of PBRM1-mutant cells, which may modulate their interactions with the immune system. However, MHC-I expression was not found to be significantly different between PBRM1 mutant and reconstituted cells. Conclusions These results shed light on changes in biology and immunogenicity associated with or caused by PBRM1 loss. They also implicate NF-kB as a potential moderator of immune response, which should be studied further to characterize its effects on immune checkpoint blockade therapy (ICB). Citation Format: Alexander Metz, Rahmat Sikder, Moataz Ellithi, Micheal Slifker, Philip Abbosh. PBRM1 loss in RCC: Implications for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3724.