SUMO2 Deletion Changes Chromatin Accessibility and Enhances Cytotoxic T Cell Activation and Tumor Infiltration [human_ATACseq]

ABSTRACT: Cytotoxic T cells (CTL) are crucial for adaptive immunity to produce prolonged survival and potential cures; however, CTL are not activated by existing immune therapies for most cancer types. Recent clinical data has shown that pharmacological inhibition of SUMOylation (SUMOi) activates CTL in the periphery and tumor microenvironment (TME) in various solid tumors, although the mechanism for SUMOi-mediated CTL activation is poorly understood. In this study, we found that T cell specific knock out (KO) of the most dominant SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation that is independent of the known mechanism – type I IFN expression by myeloid cells. Sumo2/SUMO2 KO in CD8+ T cells increased chromatin accessibility for transcription factors BATF, JunB, ATF3, FRA1, FRA2, and AP1 that promote T cell activation and proliferation. Using antigen-specific T cell models, OT1 and Chimeric Antigen Receptor (CAR)-T cells, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration as revealed by flow cytometry, immuno-fluorescence (IF) staining, and single nuclei RNA-sequencing (snRNA-seq) and conferred greater tumor growth inhibition than wildtype (WT) control T cells. snRNA-seq also revealed Sumo2 KO CD8+ T cells increased the expression of Tumor Necrosis Factor-Related Apoptosis-inducing Ligand (TRAIL) and induced apoptosis genes in tumor cells and profound changes in all cell types in the TME. These findings elucidate a novel mechanism regarding how post-translational modifications with SUMO can directly control CTL activation, tumor infiltration and cell-cell interactions in antitumor adaptive immunity. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies of solid tumors by enhancing their activity and tumor infiltration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313360 | GEO | 2026/08/18

REPOSITORIES: GEO