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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Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction
Tingting Wang,JN Rashida Gnanaprakasam,Xuyong Chen,Siwen Kang,Xuequn Xu,Hua Sun,Lingling Liu,Hayley Rodgers,Ethan Miller,Teresa Cassel,Qiushi Sun,Sara Vicente-Muñoz,Marc O. Warmoes,Penghui Lin,Zayda L Piedra-Quintero,Mireia Guerau-de-Arellano,Kevin A. Cassady,Song Guo Zheng,Jun J. Yang,Andrew N. Lane,Xiaotong Song,Teresa W.-M. Fan,Ruoning Wang +22 more
TL;DR: It is shown that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro, and that cancer cells display diverse capacities to utilize inOSine as a carbon source.
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The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy.
TL;DR: The metabolic changes that drive T cells into different stages of their development are discussed and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes are discussed.
Journal Article
STAT3 Activation-Induced Fatty Acid Oxidation in CD8
Chunyan Zhang,Chanyu Yue,Andreas Herrmann,Jieun Song,Colt Egelston,Tianyi Wang,Zhifang Zhang,Wenzhao Li,Heehyoung Lee,Maryam Aftabizadeh,Yi Jia Li,Peter P. Lee,Stephen J. Forman,George Somlo,Peiguo Chu,Laura Kruper,Joanne E. Mortimer,Dave S.B. Hoon,Wendong Huang,Saul J. Priceman,Hua Yu +20 more
TL;DR: A critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis is identified.
Journal ArticleDOI
TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy
TL;DR: How malignant tumors regulate metabolism to support their growth and survival is discussed, more recently identified metabolic profiles of different immune cell subsets andTLR-mediated regulation of cellular metabolism in both tumor and immune cells are summarized and potential strategies targeting cell metabolism for TLR-based cancer therapy are explored.
Journal ArticleDOI
A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells.
Ruihua Ma,Tiantian Ji,Huafeng Zhang,Wenqian Dong,Xinfeng Chen,Pingwei Xu,Degao Chen,Xiaoyu Liang,Xiaonan Yin,Yuying Liu,Jingwei Ma,Ke Tang,Yi Zhang,Yue'e Peng,Jinzhi Lu,Xiaofeng Qin,Xuetao Cao,Yonghong Wan,Bo Huang,Bo Huang +19 more
TL;DR: Glycogen metabolism controls memory T cells and the metabolic gene PCK1 promotes glycogen formation, which is used in the pentose phosphate pathway, generating glutathione that is important for counteraction of ROS and thus promotion of memory T-cell maintenance, and resulting in improved antitumour immunity.
References
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E. John Wherry,Volker Teichgräber,Todd C. Becker,David Masopust,Susan M. Kaech,Rustom Antia,Ulrich H. von Andrian,Rafi Ahmed +7 more
TL;DR: It is proposed that TCM and TEM do not necessarily represent distinct subsets, but are part of a continuum in a linear naive → effector → TEM → TCM differentiation pathway.
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Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T Cell Transfer Immunotherapy
Steven A. Rosenberg,James Chih-Hsin Yang,Richard M. Sherry,Udai S. Kammula,Michael S. Hughes,Giao Q. Phan,Deborah Citrin,Nicholas P. Restifo,Paul F. Robbins,John R. Wunderlich,Kathleen E. Morton,Carolyn M. Laurencot,Seth M. Steinberg,Donald E. White,Mark E. Dudley +14 more
TL;DR: Cell transfer therapy with autologous TILs can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment.
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
TL;DR: It is shown here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival.
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.
Journal ArticleDOI
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
Ryan D. Michalek,Valerie A. Gerriets,Sarah R. Jacobs,Andrew N. Macintyre,Nancie J. MacIver,Emily F. Mason,Sarah A. Sullivan,Amanda G. Nichols,Jeffrey C. Rathmell +8 more
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.