NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
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...
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| Published in | Nature immunology Vol. 22; no. 2; pp. 193 - 204 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.02.2021
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. 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 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 reprograming towards aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8 + effector T cells hypofunctional in 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 an 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 ROS levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme mediating 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 posttranslational mechanism of metabolic regulation. 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. 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. |
| Author | Xie, Xiaoping Cheng, Xuhong Zheng, Xiaofeng Brightbill, Hans D. Sohn, Jee Hyung Sun, Shao-Cong Gu, Meidi Jie, Zuliang Yang, Jin-Young Wang, Jing Zhu, Lele Zhou, Xiaofei Yang, Jie Shi, Yaoyao Kim, Jae Bum |
| AuthorAffiliation | 4 National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea 6 Present address: Precision for Medicine, Houston, Texas, USA 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas, USA 3 MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas, USA 1 Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas, USA 5 Department of Biological Sciences, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, South Korea 7 Department of Immunology, Genentech Inc., South San Francisco, California, USA |
| AuthorAffiliation_xml | – name: 7 Department of Immunology, Genentech Inc., South San Francisco, California, USA – name: 3 MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, Texas, USA – name: 6 Present address: Precision for Medicine, Houston, Texas, USA – name: 4 National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea – name: 1 Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas, USA – name: 5 Department of Biological Sciences, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, South Korea – name: 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas, USA |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33398181$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Equal contribution M.G. designed and performed the research, prepared the figures, and wrote part of the manuscript; X.Zhou. designed and performed the research and prepared the figures; L.Z., Z.J, J.-Y.Y., X.X., J.Y., Y.S., and X.C. contributed experiments; X.Zheng. and J.W. performed the RNA sequencing data analysis; J.H.S. and J.B.K. contributed G6PDmut mouse materials; H.D.B. contributed Map3k14 flox mice; and S-C.S. supervised the work and wrote the manuscript. Author Contributions |
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| PublicationDateYYYYMMDD | 2021-02-01 |
| PublicationDate_xml | – month: 02 year: 2021 text: 2021-02-01 day: 01 |
| PublicationDecade | 2020 |
| PublicationPlace | New York |
| PublicationPlace_xml | – name: New York – name: United States |
| PublicationTitle | Nature immunology |
| PublicationTitleAbbrev | Nat Immunol |
| PublicationTitleAlternate | Nat Immunol |
| PublicationYear | 2021 |
| Publisher | Nature Publishing Group US Nature Publishing Group |
| Publisher_xml | – name: Nature Publishing Group US – name: Nature Publishing Group |
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| Snippet | Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK)... Metabolic reprograming towards aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show deficiency in NF-κB-inducing kinase (NIK)... |
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| SubjectTerms | 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 |
| Title | NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity |
| URI | https://link.springer.com/article/10.1038/s41590-020-00829-6 https://www.ncbi.nlm.nih.gov/pubmed/33398181 https://www.proquest.com/docview/2480547196 https://www.proquest.com/docview/2475399692 https://pubmed.ncbi.nlm.nih.gov/PMC7855506 |
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