Abstract 5737: Genomic drivers of cancer are enriched and mutually exclusive within non-T cell-inflamed tumors

Abstract

Abstract While immunotherapy has seen dramatic successes in a variety of malignancies, the majority of patients fail to respond. In particular, less than 10% of patients with metastatic, castrate-resistant prostate cancer (mCRPC) respond to immunotherapy. Based on previous work demonstrating robust clinical activity of immunotherapies in patients with a T cell-inflamed tumor microenvironment, we investigated whether non-T cell-inflamed cancers show evidence for distinct genomic alterations that might mediate immune escape. RNA-seq gene expression data were analyzed from two prostate cancer cohorts, The Cancer Genome Atlas (TCGA) of primary tumors (n=437) and a Stand Up to Cancer (SU2C) mCRPC cohort (n=43). These datasets were interrogated for common molecular alterations and their association with non-T cell-inflamed and T cell-inflamed cancers, focusing on copy number deletions of PTEN, RB1/CDKN2A, and activating mutations in CTNNB1 (β-catenin). Similar approaches were used to analyze 30 solid tumor types from TCGA (n=9555). Our analysis identified that 94% of primary prostate cancers harbor a non-T cell-inflamed tumor microenvironment, with only 6% of patients having a T cell-inflamed gene signature. Similar results were found in mCRPC patients from the SU2C cohort. Higher frequencies of PTEN loss and CTNNB1 activation, as well as a significant enrichment of RB1/CDKN2A deletion, were found in non-T cell-inflamed primary and metastatic prostate tumors. Moreover, we observed a direct correlation between the expression of PTEN/RB1 and CD8A expression within the tumor microenvironment. Strikingly, analysis of 30 human cancers revealed that loss of PTEN and/or RB1/CDKN2A correlates with T-cell exclusion across multiple malignancies. When combined with β-catenin pathway activation, we found that these alterations are mutually exclusive, with only 1% of non-T cell-inflamed cancers sharing all three mechanisms, 24% sharing two out of the three, and 75% of the samples harboring only one mechanism. Taken together, these data reveal that deregulated PTEN/PI3K, Rb and Wnt-β-catenin signaling networks are enriched in a mutually exclusive manner within non-T cell-inflamed cancers, suggesting that such cancers evolutionarily co-opt nonredundant signaling pathways to achieve a common goal of immune evasion. Targeting these pathways pharmacologically may provide an opportunity to enhance responsiveness to immunotherapy across multiple malignancies. Citation Format: Brian Olson, Riyue Bao, Jessica Fessler, Jason Luke, Thomas F. Gajewski, Akash Patnaik. Genomic drivers of cancer are enriched and mutually exclusive within non-T cell-inflamed tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5737.