PRDX1 regulates T cell effector function in the ovarian tumor microenvironment
McPhedran, S. J.; Carleton, G.; Hannan, S.; MacPherson, S.; Castro, L.; Preshaw, S.; Lum, J.
Show abstract
T cell-based immunotherapies have remained ineffective against high-grade serous ovarian carcinoma (HGSOC). The metabolic environment of HGSOC suppresses the activity of cellular therapies, however, the metabolites that enhance or suppress T cell antitumor activity are not fully understood. Here, a pooled CRISPR-Cas9 knockout screen in primary human T cells cultured with patient-derived ascites was used to identify metabolic enzymes that inhibit effector cytokine production and cytolytic function. The screen identified PRDX1 as a negative regulator of T cell effector function. Targeted deletion of PRDX1 increased the frequency of IFN-{gamma}-producing T cells, enhanced glucose uptake, increased mitochondrial mass, and improved T cell viability under suppressive ascites conditions. Mechanistically, PRDX1 deficiency increased intracellular reactive oxygen species (ROS) and impaired autophagic flux. The effects of PRDX1 deletion enhanced aspects of T cell function, while its effects on chimeric antigen receptor (CAR)-T cell cytotoxicity were donor dependent. Collectively, this study identifies PRDX1 as a regulator of T cell activation, metabolism, and effector function in the inhibitory physiological suppressive environment of HGSOC ascites.
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