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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Inhibition of the lymphocyte metabolic switch by the oxidative burst of human neutrophils.
Philip A. Kramer,Lynn Prichard,Balu K. Chacko,Saranya Ravi,E. Turner Overton,Sonya L. Heath,Victor M. Darley-Usmar +6 more
TL;DR: It is shown that the lymphocyte metabolic switch from mitochondrial respiration to glycolysis is prevented by the oxidative burst of neutrophils, which is a likely mechanism underlying the neutrophil-dependent suppression of T-cell effector function.
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In Vitro-Generated Tc17 Cells Present a Memory Phenotype and Serve As a Reservoir of Tc1 Cells In Vivo.
Felipe Flores-Santibáñez,Bárbara Cuadra,Dominique Fernández,M. Rosemblatt,M. Rosemblatt,Sarah Nuñez,Pablo Cruz,Felipe Gálvez-Cancino,J. César Cárdenas,Alvaro Lladser,Mario Rosemblatt,Mario Rosemblatt,María Rosa Bono,Daniela Sauma +13 more
TL;DR: It is demonstrated that in vitro-generated Tc17 cells acquire a central memory program and provide a lasting reservoir of Tc1 cells in vivo, thus supporting the use of T c17 lymphocytes in the design of novel and more effective therapies.
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TGFβ programs central-memory differentiation in ex vivo-stimulated human T cells
Amina Dahmani,Valérie Janelle,Cédric Carli,Manon Richaud,Caroline Lamarche,Caroline Lamarche,Myriam Khalili,Mathieu Goupil,Ksenia Bezverbnaya,Jonathan L. Bramson,Jean-Sébastien Delisle,Jean-Sébastien Delisle +11 more
TL;DR: It is reported that exposure to exogenous TGFβ during human T-cell stimulation ex vivo leads to the accumulation of early/central memory (Tcm) cells, and indicates that TGF β signaling may be harnessed to program Tcm differentiation in the context of ex vivo T- cell stimulation for adoptive immunotherapy in humans.
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The Acidic Brain-Glycolytic Switch in the Microenvironment of Malignant Glioma.
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Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect
TL;DR: It is believed that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.
References
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Journal ArticleDOI
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Journal ArticleDOI
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Ruoning Wang,Christopher P. Dillon,Lewis Zhichang Shi,Sandra Milasta,Robert Carter,David Finkelstein,Laura L. McCormick,Patrick Fitzgerald,Hongbo Chi,Joshua Munger,Douglas R. Green +10 more
TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
Journal ArticleDOI
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
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TL;DR: Teff and Treg were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation.