Exogenous catalase treatment enhances CD8+T cell functionality and hinders T cell exhaustion

Abstract ROS are small short-lived oxygen-containing molecules which are highly chemically reactive and involved in the regulation of biological processes like T cell activation and proliferation. The tumor microenvironment (TME) is a metabolically hostile environment with a deficiency in nutrients like glucose and glutamine, accumulation of tumor-driven metabolic waste, and extreme hypoxia. Hypoxia results in impaired mitochondrial function and generation of excess levels of ROS, which have been known to promote T cell exhaustion. Here, we investigated how exogenous treatment of antioxidant catalase altered CD8+ T cell effector responses and T cell exhaustion using OT-I TCR transgenic mice. During CD8+ T cell effector differentiation in vitro by stimulation with cognate antigen followed by culture with IL-2, addition of catalase significantly enhanced T cell activation and effector differentiation. Catalase-treated effector cells had higher expression of critical activation markers including CD69 and CD25, increased expression of the stemness marker TCF-1, and enhanced secretion of effector cytokines IFNγ and TNFα. During induction of T cell exhaustion in vitro by co-culture with B16 melanoma expressing ovalbumin (B16-Ova), catalase-treated OT-I T cells had significantly increased cytotoxic activity, enhanced expression of CD25 and lower co-expression of PD-1 and TIM-3 relative to non-treated OT-I T cells. Our findings uncover a new role for catalase in altering the fate of CD8+ effector T cells and potentially a new therapeutic tool for managing T cell exhaustion. NIH (R01 CA212605)