NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity

• Published in: Nature immunology Vol. 22; no. 2; pp. 193 - 204
• Main Authors: Gu, Meidi, Zhou, Xiaofei, Sohn, Jee Hyung, Zhu, Lele, Jie, Zuliang, Yang, Jin-Young, Zheng, Xiaofeng, Xie, Xiaoping, Yang, Jie, Shi, Yaoyao, Brightbill, Hans D., Kim, Jae Bum, Wang, Jing, Cheng, Xuhong, Sun, Shao-Cong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/250/516; 631/250/580; Animals; Antioxidants; Antitumor activity; Biomedical and Life Sciences; Biomedicine; CD8 antigen; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Line, Tumor; Colonic Neoplasms - enzymology; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Cytotoxicity; Cytotoxicity, Immunologic; Ectopic expression; Effector cells; Energy Metabolism; Enzyme Stability; Enzymes; Female; Fitness; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - metabolism; Glycolysis; Hexokinase; Hexokinase - genetics; Hexokinase - metabolism; Immunity; Immunology; Immunotherapy, Adoptive; Infectious Diseases; Kinases; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - enzymology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - transplantation; Male; Melanoma, Experimental - enzymology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NADP - metabolism; NF-kappaB-Inducing Kinase; NF-κB protein; Phenotype; Post-translation; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction; Tumor Microenvironment
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-00829-6

Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8 + effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8 + T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD–NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation. Metabolic rewiring of cytotoxic T lymphocytes (CTLs) can impair their antitumor functions. Sun and colleagues demonstrate that CTL-intrinsic activity of the kinase NIK is essential for CTL metabolic fitness in the tumor microenvironment.