Metabolically improving the generation, function, and persistence of therapeutic T cells for the treatment of cancer

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Project Summary Immunotherapy has shifted the paradigm in the understanding and treatment of cancer. Within this arsenal of new treatment strategies, adoptive cell therapy (ACT) has shown great promise; however, several barriers to efficacy remain. One major hurdle is the high metabolic requirements of T cell anti-tumor cytoxicity within the nutrient-poor tumor microenvironment (TME). Current culturing strategies used to generate high numbers of T cells in vitro exacerbate this problem by using hyperglycemic and hyperoxic culture conditions. This strategy favors the metabolic needs of T cells during expansion but ignores their metabolic requirements for persistence within the TME. Our preliminary data indicate that treatment with the pyruvate dehydrogenase kinase 1 (PDHK1) inhibitor dichloroacetate (DCA) during in vitro expansion of therapeutic T cells maintains therapeutic T cell proliferation while improving anti-tumor clearance in vivo. Intriguingly, transcriptomic analysis of DCA-treated T cells reveals a downregulation of interferon-stimulated genes (ISGs) seen in response to mitochondrial DNA (mtDNA) damage. We hypothesize that DCA shunts glycolysis in a manner that re-directs metabolism to a more oxidative state and thus prevents T cell mitochondrial stress and mtDNA releases during initial expansion allowing for more fit T cells pre-infusion. Within this study, we aim to determine how DCA’s metabolic effects and abrogation of ISGs contribute to improved anti-tumor efficacy. Determining the mechanism of action of DCA on therapeutic T cells will not only inform the field of the benefits of using DCA as an in vitro culture supplement for the generation of more efficacious therapeutic T cells, but will also allow for a better understanding of the biological requirements for T cell function overall.