Inhibition of histone methyltransferase EZH2 for immune interception of colorectal cancer in Lynch syndrome

Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 over 9 weeks notably reduced adenoma multiplicity, demonstrating its efficacy as a preventive modality. Single-cell RNA-Seq and molecular analyses showed activation of immune and apoptotic markers, along with a reduction in H3K27 methylation levels in colonic crypts. ChIP sequencing further revealed decreased levels of H3K27me3 and H3K4me1, while levels of the active enhancer marks H3K4me3 and H3K27Ac increased in treated mice. Collectively, these findings indicate that EZH2 inhibition enhances immune responses through epigenetic reprogramming in the genome of LS mice, establishing a promising framework for the clinical development of EZH2 inhibitors as a cancer prevention strategy for LS carriers.