Modulating the ER and Golgi stress response in T cells with hydrogen sulfide signaling to enhance the anti-tumor immune response

Abstract Adoptive cell therapy (ACT) continues to emerge as a novel therapeutic strategy for treating cancer. New approaches to improve ACT protocols are needed to enhance in vivo persistence of adoptively transferred tumor antigen-specific T cells and overcome tumor-induced immunosuppression and cellular stress. Here, we show that hydrogen sulfide (H 2S) can be used to promote the antitumor immune response using an H 2S donor compound and by enhancing endogenous production of H 2S with overexpression of Cbs, a key H 2S-producing enzyme. Expansion of tumor antigen-specific T cells with exogenous H 2S promoted a central memory phenotype with enhanced antioxidant capacity. H 2S-treated T cells and T cells overexpressing Cbs also displayed enhanced reactivity to tumor antigen, with an increase in production of cytolytic cytokines and increased overall protein translation. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H 2S demonstrated superior tumor control upon ACT. Proteomics analysis revealed an increase in protective thiol modifications on ER-associated proteins involved in regulating ER stress in T cells treated with H 2S. Further, treatment of antitumor T cells with H 2S resulted in resistance to Golgi and ER stress. Golgi stress and overall Golgi mass were identified as important determinants of T cell function, with T cells possessing high Golgi mass exerting more robust tumor control when adoptively transferred. Overall, these data show that antitumor T cells exposed to H 2S possess an enhanced antitumor phenotype that allows them to exert greater tumor control in ACT. Further, these studies identify the status of the Golgi in T cells as an important determinant of their antitumor capacity. R01 CA236379