KDM6A Mutation Defines Divergent Responses to Chemotherapy and Immunotherapy
Retrospective analysis of patient cohorts revealed that KDM6A mutation status correlates with divergent outcomes depending on treatment modality. Patients harboring KDM6A mutations had significantly worse overall survival following cisplatin-based chemotherapy, whereas those same patients demonstrated improved overall survival when treated with anti PD1/PD-L1 therapy in the IMvigor210 cohort. This context dependent relationship between KDM6A mutation and therapeutic outcome motivated a systematic mechanistic investigation using CRISPR engineered human and murine bladder cancer models.
Cisplatin Resistance: eccDNA Accumulation as a Downstream Consequence of KDM6A Loss
Whole genome sequencing of KDM6A knockout human bladder cancer cells revealed genome wide copy number gains and accumulation of extrachromosomal circular DNA (eccDNA). These circular amplicons carry genes with established roles in cisplatin resistance, including TP63, CLDN4, GLI2, LUC7L3, ERCC4, and SHCBP1. Analysis of TCGA BLCA patient data corroborated these findings, with KDM6A mutant tumors showing increased circular amplicons and upregulation of POLQ, a key mediator of eccDNA biogenesis. Functionally, KDM6A deficient cells demonstrated reduced cisplatin induced cytotoxicity and increased invasion, migration, and spheroid formation compared to controls. Together, these data link KDM6A loss to structural genomic instability and cisplatin resistance through eccDNA mediated oncogene amplification.
Immunotherapy Sensitivity: Epigenetic Regulation of DNA Repair
KDM6A loss also impairs the transcription of genes involved in mismatch repair. ChIP seq analysis demonstrated direct KDM6A binding at the promoters of repair genes, including MSH2, MSH6, EXO1, and LIG3, with loss of KDM6A resulting in increased H3K27me3 and decreased H3K4me3 enrichment at these loci. Transcriptional repression of these repair programs was confirmed at both the mRNA and protein levels. Functionally, KDM6A deficient tumors displayed microsatellite instability and elevated tumor mutation burden in patient cohorts. Importantly, these changes occur in the absence of co-occurring mutations in canonical MMR or DSBR genes, indicating that KDM6A independently regulates these pathways through epigenetic mechanisms rather than direct mutational inactivation.
Metabolic Reprogramming and the Tumor Immune Microenvironment
In addition to its effects on genomic stability and DNA repair, KDM6A regulates tumor cell metabolism. KDM6A deficient tumors showed reduced expression of glycolytic enzymes, decreased glycolytic ATP production, and diminished lactate accumulation in the tumor interstitial fluid, alongside upregulation of oxidative phosphorylation. This reduction in intratumoral lactate had downstream consequences for the immune microenvironment. Regulatory T cells (Tregs) in the tumor microenvironment take up extracellular lactate, which drives histone lactylation at H3K9 and H3K18,3 promoting expression of immunosuppressive genes, including Foxp3, Tgfb, and Pdcd1. In KDM6A deficient tumors, reduced lactate availability attenuated histone lactylation in intratumoral Tregs, decreased PD1 expression, and limited Treg expansion following anti PD1 therapy. The net result was an improved effector CD8 T cell to Treg ratio and enhanced response to immune checkpoint therapy in preclinical models of bladder cancer.
Summary and Clinical Implications
Our findings establish KDM6A as an epigenetic regulator that integrates genomic stability, DNA repair, and tumor metabolism to govern therapeutic responses in bladder cancer. Its loss promotes cisplatin resistance through eccDNA driven oncogene amplification while enhancing immunotherapy sensitivity through impaired DNA repair and reduced intratumoral lactate production.
From a clinical standpoint, these findings provide a mechanistic framework for incorporating KDM6A mutation status into therapeutic stratification strategies in advanced bladder cancer, warranting prospective clinical validation.
Written by: Sangeeta Goswami, MD, PhD, Associate Professor, Genitourinary Medical Oncology and Immunology, Member, James P. Allison Institute, Faculty, Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center, Houston, TX
References:
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- Raychaudhuri, D. et al. Histone lactylation drives CD8(+) T cell metabolism and function. Nat Immunol 25, 2140-2151, doi:10.1038/s41590-024-01985-9 (2024).