Mounting evidence has revealed a dynamic metabolic crosstalk between cancer cells and T cells. It is evident that the metabolic constraints imposed by cancer cells compromise T-cell metabolic fitness and render T cells dysfunctional even in the face of antigenic stimulation. However, whether and how T cells affect tumor cell metabolism remains unclear. In the present study, we report that adoptive transfer of tumor-specific CD4+ T cells following CTX preconditioning gave rise to polyfunctional CD4+ effector cells capable of concomitantly producing multiple inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon gamma (IFNγ). These CD4+ effector cells induced profound metabolic changes in tumors before tumor regression was evident. Disruptions in multiple metabolic pathways converged to cause defective synthesis of the major cellular antioxidant glutathione (GSH), resulting in severe GSH deficiency, heightened reactive oxygen species (ROS) accumulation, and oxidative DNA damage in tumor cells. We demonstrated that tumor cell-intrinsic TNF-α signaling was required to synergize with chemotherapy to intensify ROS production in tumor via a mechanism involving nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases. Our data provide new insight into the impact of an effective immunotherapy on tumor metabolism and identify tilting tumor redox toward excessive oxidative stress as an important mechanism underlying the efficacy of adoptive immunotherapy.

Citation Format: Gang Zhou, Tsadik Habetesion, Zhi-Chun Ding. Alteration of tumor metabolism by antitumor CD4+ T cells leads to tumor rejection [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A56.