Inhibiting glycolytic metabolism enhances CD8⁺ T cell memory and antitumor function

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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.

Authors

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