Abstract A04: DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer

Abstract

Abstract Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behavior of cancer cells and their adaptation to the coevolving microenvironment and response to treatment. In alignment with this concept, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR). A comprehensive understanding of DDR mutation-associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. We thus investigated the pretreatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle-invasive urothelial cancer (MIUC; n=408) from the Genomic Data Commons, to determine subtype-specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene mutation profiles. Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune-stimulatory and -inhibitory genes showed significant associations with subtypes and DDR mutation status. Findings from our study provide compelling evidence for coexpression of multiple immune checkpoint genes including PD-1, PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies. Citation Format: Thiago Vidotto, Sarah Nersesian, Charles Graham, David Robert Siemens, Madhuri Koti. DNA damage repair gene mutations and associated tumor immune landscape as biomarkers of response to immunotherapy in muscle-invasive urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A04.