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
Citations
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Regulatory circuits of T cell function in cancer
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Veronica Huber,Chiara Camisaschi,Angela Berzi,Simona Ferro,Luana Lugini,Tiziana Triulzi,Alessandra Tuccitto,Elda Tagliabue,Chiara Castelli,Licia Rivoltini +9 more
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Marc O. Johnson,Marc O. Johnson,Melissa M. Wolf,Matthew Z. Madden,Gabriela Andrejeva,Ayaka Sugiura,Diana C. Contreras,Damian Maseda,Maria V. Liberti,Katelyn Paz,Rigel J. Kishton,Matthew E. Johnson,Aguirre A. de Cubas,Pingsheng Wu,Gongbo Li,Yongliang Zhang,Dawn C. Newcomb,Andrew D. Wells,Nicholas P. Restifo,W. Kimryn Rathmell,W. Kimryn Rathmell,Jason W. Locasale,Marco L. Davila,Bruce R. Blazar,Jeffrey C. Rathmell,Jeffrey C. Rathmell +25 more
TL;DR: Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells.
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Xiaoyun Li,Mathias Wenes,Pedro Romero,Stanley Ching-Cheng Huang,Sarah-Maria Fendt,Sarah-Maria Fendt,Ping-Chih Ho +6 more
TL;DR: An overview of the pathways of cancer metabolism that intersect with immunometabolism, typically resulting in immunosuppression, is provided, with a focus on how these metabolic pathways could be targeted in order to enhance anticancer immunity and immunotherapy.
References
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Journal ArticleDOI
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chih-Hao Chang,Jonathan D. Curtis,Leonard B. Maggi,Brandon Faubert,Alejandro V. Villarino,David O’Sullivan,Stanley Ching-Cheng Huang,Gerritje J.W. van der Windt,Julianna Blagih,Jing Qiu,Jason D. Weber,Edward J. Pearce,Russell G. Jones,Erika L. Pearce +13 more
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Journal ArticleDOI
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
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.
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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.