Background: 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 behaviour of cancer cells and their adaptation to the co-evolving microenvironment and response to treatment. In alignment with these concepts, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR) genes. A comprehensive understanding of DDR gene inactivation 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.
Methods: We investigated pre-treatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle invasive urothelial cancer (MIUC; n = 408) from The Cancer Genome Atlas, to determine subtype specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene inactivation (via mutation, copy number alteration) profiles.
Results: 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 gene mutation status.
Conclusion: Findings from our study provide compelling evidence for co-expression 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.
Keywords: Bladder Cancer; DNA damage repair; Immune checkpoint; Interferon.