Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Madhusudhanan Sukumar,Jie Liu,Yun Ji,Murugan Subramanian,Joseph G. Crompton,Zhiya Yu,Rahul Roychoudhuri,Douglas C. Palmer,Pawel Muranski,Edward D. Karoly,Robert P. Mohney,Christopher A. Klebanoff,Ashish Lal,Toren Finkel,Nicholas P. Restifo,Luca Gattinoni +15 more
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TLDR
It is indicated that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+, and the efficacy of T cell-based therapies against chronic infectious diseases and cancer.Abstract:
Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell–based therapies against chronic infectious diseases and cancer.read more
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L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity.
Roger Geiger,Roger Geiger,Jan C. Rieckmann,Tobias Wolf,Tobias Wolf,Camilla Basso,Yuehan Feng,Tobias Fuhrer,Maria Kogadeeva,Paola Picotti,Felix Meissner,Matthias Mann,Nicola Zamboni,Federica Sallusto,Antonio Lanzavecchia,Antonio Lanzavecchia +15 more
TL;DR: Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity.
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T cell metabolism drives immunity
TL;DR: The role of lymphocyte metabolism on immune cell development and function and the importance of “goodtenance” in immune cell function is discussed.
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Metabolic Instruction of Immunity
TL;DR: This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.
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A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
Daniela S. Thommen,Daniela S. Thommen,Viktor H. Koelzer,Petra Herzig,Andreas Roller,Marcel P. Trefny,Sarah Dimeloe,Anna Kiialainen,Jonathan C Hanhart,Catherine Schill,Christoph Hess,Spasenija Savic Prince,Mark Wiese,Didier Lardinois,Ping-Chih Ho,Christian Klein,Vaios Karanikas,Kirsten D. Mertz,Ton N. Schumacher,Alfred Zippelius +19 more
TL;DR: The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
Journal ArticleDOI
Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments
Alessia Angelin,Luis Gil-de-Gómez,Satinder Dahiya,Jing Jiao,Lili Guo,Matthew H. Levine,Zhonglin Wang,William J. Quinn,Piotr K. Kopinski,Piotr K. Kopinski,Liqing Wang,Tatiana Akimova,Yujie Liu,Tricia R. Bhatti,Rongxiang Han,Benjamin L. Laskin,Joseph A. Baur,Ian A. Blair,Douglas C. Wallace,Douglas C. Wallace,Wayne W. Hancock,Ulf H. Beier +21 more
TL;DR: It is reported that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation, which allows Tregs a metabolic advantage in low-glucose, lactate-rich environments.
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