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Hydrogen sulfide signaling in promoting the anti-tumor T cell response
Ist Teil von
The Journal of immunology (1950), 2022-05, Vol.208 (1_Supplement), p.119-119.09
Erscheinungsjahr
2022
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Abstract
Adoptive cell therapy (ACT), a form of immunotherapy, continues to emerge as a novel therapeutic strategy for treating advanced malignancies. 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 oxidative stress, which remain significant barriers to the clinical success of ACT. Here, we show that exogenous hydrogen sulfide (H2S), an important gaseous signaling molecule, promoted a central memory phenotype with enhanced antioxidant capacity in tumor antigen-specific T cells. In vitro, T cells treated with exogenous H2S upregulated key antioxidant enzymes and molecules associated with stemness while simultaneously downregulating immune checkpoint molecules. H2S-treated T cells also displayed an enhanced reactivity to tumor antigen, with an increase in production of pro-inflammatory cytokines as well as an increase in overall protein translation. H2S-treated T cells also displayed an enhanced ability to combat oxidative stress, with a reduced accumulation of reactive oxygen species and protection against hydrogen peroxide-induced cell death. In an in vivo murine model of melanoma, tumor-reactive T cells conditioned ex vivo with exogenous H2S demonstrated superior tumor control upon ACT. Even greater tumor control was observed when ACT-treated mice were injected systemically with an H2S donor compound. These data provide evidence that anti-tumor T cells exposed to H2S possess an enhanced metabolic and stem-like phenotype that allows them to persist in the immunosuppressive tumor microenvironment and exert greater tumor control upon adoptive transfer into tumor-bearing hosts.
Supported by NIH R01 CA236379