Abstract A32: The SUV39H1-H3K9me3 pathway represses cytotoxic T lymphocyte effector expression to confer colon carcinoma immune escape

Abstract

Abstract Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancers do 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 are present in both MSI and microsatellite stable (MSS) colon tumors. The expression of the H3K9me3-specific histone methyltransferase SUV39H1 is significantly elevated in human colon carcinoma as compared to normal colon tissues. Using a mouse colon carcinoma model, we further determined that tumor-infiltrating CTLs in the colon tumor microenvironment express high levels of SUV39H1. To target SUV39H1 in the tumor microenvironment, a virtual chemical library was screened based on the SET domain structure of 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 novel small molecule, termed F5446, which has an EC50 of 0.496 μM for SUV39H1 enzymatic activity. H3K9me3 is enriched in the promoters of GZMB, PRF1, FASLG and IFNG in quiescent T cells. F5446 inhibits 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 expression and, in doing so, confers colon cancer immune escape. Citation Format: Chunwan Lu, Dafeng Yang, John D. Klement, II Kyu Oh, Natasha M. Savage, Jennifer L. Waller, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric Pearce, Zhiliang Xie, Samuel Kulp, Christopher Coss, Mitch A. Phelps, Thomas Albers, Iryna O. Lebedyeva, Kebin Liu. The SUV39H1-H3K9me3 pathway represses cytotoxic T lymphocyte effector expression to confer colon carcinoma immune escape [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A32.