SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration.

Cytotoxic T cells [cytotoxic lymphocytes (CTLs)] are crucial for adaptive immunity leading to prolonged survival and potential cures for cancer. Recent clinical data have shown that pharmacological inhibition modifies the tumor microenvironment (TME) and activates CTLs, although the mechanism is not well described. In this study, we found that T cell-specific knockout (KO) of the most prevalent SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation without enhanced IFN-I (type I interferon)-responsive genes in vitro but increased chromatin accessibility at enhancer regions for AP-1 (activating protein 1) family members, including BATF and JunB, which are known to promote T cell activation and proliferation. Using antigen-specific OT1 and CAR (chimeric antigen receptor) T cell models, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration, as revealed by flow cytometry, immunofluorescence staining, and single-nucleus RNA sequencing (snRNA-seq), and conferred greater tumor growth inhibition than wild-type control T cells. snRNA-seq also revealed that Sumo2 KO in CD8+ T cells increased the expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in vivo and activated the antitumor immune microenvironment, likely through cell-cell interaction involving more activated CTLs. These findings elucidate a novel mechanism by which SUMOylation controls CTL activation and tumor infiltration that activate antitumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies for solid tumors by enhancing their activation, tumor infiltration and ability to modulate the TME.