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

Tsadik Habtetsion, Zhi Chun Ding, Wenhu Pi, Tao Li, Chunwan Lu, Tingting Chen, Caixia Xi, Helena Spartz, Kebin Liu, Zhonglin Hao, Nahid Mivechi, Yuqing Huo, Bruce R. Blazar, David H. Munn, Gang Zhou

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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 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. 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.

Original languageEnglish (US)
Pages (from-to)228-242.e6
JournalCell Metabolism
Volume28
Issue number2
DOIs
StatePublished - Aug 7 2018

Bibliographical note

Funding Information:
We thank the Georgia Cancer Center FACS and Imaging Core Facility for cell sorting and imaging analysis. We appreciate the advice from Drs. T. Johnson, Y. He, and M. Shimoda. We thank Dr. H. Xu for assistance in statistical analysis. We are grateful for the technical support provided by Drs. P. Rodriguez, J. Trillo-Tinoco, M. Khan, and S. Vyas. This work was supported by NIH grants R01CA158202 and 1R01CA215523 , and the American Cancer Society Research Scholar Grant ( RSG-12-169-01-LIB ) to G.Z., and R01 HL11879 to B.R.B.

Keywords

  • CD4+ T cell
  • NADPH oxidase
  • TNF-α
  • adoptive immunotherapy
  • chemotherapy
  • glutathione
  • metabolism
  • oxidative stress
  • reactive oxygen species
  • redox

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