Abstract 1533: CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction

Abstract The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal cancer. By conducting metabolic profiling on resected tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) along with increased oxidative DNA damages. We further demonstrate that T cell-derived TNFα can synergize with chemotherapy to drive heightened oxidative stress and tumor cell death. Reduction of oxidative stress, by neutralizing TNFα or scavenging ROS, antagonized the therapeutic effects of adoptive T-cell therapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effect of T-cell transfer. Furthermore, T cell-induced oxidative stress in tumor was observed in several different tumor models. These findings imply that tumor redox modulation represents an important mechanism underlying the efficacy of adoptive immunotherapy. Citation Format: Gang Zhou, Tsadik Habtetsion, Zhi-Chun Ding. CD4+ T cells reprogram tumor metabolism and drive oxidative stress-induced tumor destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1533.