Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

• Published in: Cell metabolism 2018-08, Vol.28 (2), p.228-242.e6
• Main Authors: Habtetsion, Tsadik, Ding, Zhi-Chun, Pi, Wenhu, Li, Tao, Lu, Chunwan, Chen, Tingting, Xi, Caixia, Spartz, Helena, Liu, Kebin, Hao, Zhonglin, Mivechi, Nahid, Huo, Yuqing, Blazar, Bruce R., Munn, David H., Zhou, Gang
• Format: Article
• Language: English
• Subjects: adoptive immunotherapy; Animals; Apoptosis - drug effects; CD4+ T cell; CD4-Positive T-Lymphocytes - physiology; Cell Line, Tumor; chemotherapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; glutathione; Glutathione - metabolism; Immunotherapy, Adoptive - methods; metabolism; Mice; Mice, Inbred BALB C; NADPH oxidase; NADPH Oxidases - metabolism; oxidative stress; Oxidative Stress - drug effects; reactive oxygen species; Reactive Oxygen Species - metabolism; redox; Signal Transduction - drug effects; TNF-α; Tumor Necrosis Factor-alpha - metabolism; Xenograft Model Antitumor Assays - methods
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.05.012

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 tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy. [Display omitted] •Adoptive CD4+ T cell therapy in mice induces extensive metabolic changes in tumor•Immunotherapy leads to glutathione deficiency and oxidative DNA damage in tumor•TNF-α and chemotherapy synergize to intensify ROS levels in tumor via NADPH oxidase•Reducing tumor oxidative stress diminishes the efficacy of adoptive T cell therapy Using a preclinical model of colorectal tumors treated with CD4+ T cell-based adoptive immunotherapy, Habtetsion et al. show that profound metabolic changes occur in tumors before tumor regression. T cells shape tumor metabolism through TNF-α, which can synergize with chemotherapy, to increase tumor cell oxidative stress through an NOX-dependent mechanism.