Abstract 4834: Genomic and metabolic effects of KDM6A loss regulates differential responses to immune checkpoint therapy and chemotherapy in bladder cancer

Abstract Bladder cancer often harbors driver mutations in genes regulating epigenetic processes, yet their influence on therapeutic perturbations is understudied. One key example is KDM6A, a gene frequently mutated in bladder cancer, which encodes a histone demethylase that confers transcription permissive chromatin state. Retrospective analysis of patient cohorts demonstrated that KDM6A mutations correlate with improved response to immune checkpoint therapy (ICT) and decreased sensitivity to cisplatin-based chemotherapy. Mechanistic studies reveal that CRISPR-Cas9 deletion of Kdm6a reduced expression of critical genes including Msh2, Msh6, and Exo1 involved in DNA Mismatch repair (MMR) and double-stranded base repair (DSBR) in tumor cells with improved response to anti-PD-1 therapy. Further, KDM6A deficiency downregulated genes involved in cisplatin resistance and attenuated sensitivity to cisplatin-based chemotherapy in vitro and in vivo. Additionally, loss of KDM6A was associated with metabolic shift from glycolysis to oxidative phosphorylation. CyTOF analyses show decreased abundance regulatory T cells (Tregs) in Kdm6a-knockout tumors. Importantly, reduced lactate in the Kdm6a-knockout tumor microenvironment impaired histone lactylation (H3K9la/H3K18la) in Tregs with concurrent attenuation of expression of key immunosuppressive genes including Foxp3, Tgfß1 and Pdcd1. Collectively, this study provided insights into the role of KDM6A-mediated epigenetic regulation of DNA repair and metabolic reprogramming which could potentially govern response to chemotherapy and ICT aiding patient stratification and development of personalized treatment algorithms. Citation Format: Pratishtha Singh, Deblina Raychaudhuri, Bidisha Chakraborty, Aminah J. Tannir, Swadhin Meher, Anurag Majumdar, Jessalyn Hawkins, Yun Xiong, Philip L. Lorenzi, Padmanee Sharma, Patrick G. Pilie, Sangeeta Goswami. Genomic and metabolic effects of KDM6A loss regulates differential responses to immune checkpoint therapy and chemotherapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4834.