SUV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion
Menée à l'aide de modèles murins de carcinome du côlon, cette étude met en évidence un mécanisme par lequel l'histone méthyltransférase SUV39H1 réprime l'expression de gènes codant pour des protéines impliquées dans l'activité des lymphocytes T cytotoxiques intratumoraux et favorise ainsi l'échappement immunitaire de la tumeur
Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that CTLs were present in both MSI and microsatellite stable (MSS) colon tumors. The expression of the H3K9me3-specific histone methyltransferase SUV39H1 was significantly elevated in human colon carcinoma compared to normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment have high expression of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened based on the SET (suppressor of variegation 3-9, enhancer of zeste and trithorax) domain structure of the human SUV39H1 protein. Functional enzymatic activity assays identified a small molecule that inhibits SUV39H1 enzymatic activity. Based on the structure of this small molecule, we modified it and chemically synthesized a small molecule, termed F5446, which has an EC50 of 0.496 µM for SUV39H1 enzymatic activity. H3K9me3 was enriched in the promoters of GZMB, PRF1, FASLG, and IFNG in quiescent T cells. F5446 inhibited H3K9me3, thereby, upregulating expression of these effectors in tumor-infiltrating CTLs and suppressing colon carcinoma growth in a CD8+ CTL-dependent manner in vivo. Our data indicate that SUV39H1 represses CTL effector gene expression and, in doing so, confers colon cancer immune escape.