Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Patrick M Gubser; Sharanya Wijesinghe; Leonie Heyden; Sarah S Gabriel; David P de Souza; Christoph Hess; Malcolm M McConville; Daniel T Utzschneider; Axel Kallies

Journal article

Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies

Cell Reports | Elsevier | Published : 2024

DOI: 10.1016/j.celrep.2024.114632

Abstract

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 ca..

View full abstract

University of Melbourne Researchers

David de Souza Author

Malcolm McConville Author

Daniel Utzschneider Author

Axel Kallies Author

Related Projects (2)

REGULATION OF METABOLIC DYSFUNCTION AND EXHAUSTION OF VIRUS-SPECIFIC T CELLS DURING CHRONIC INFECTION

T cells control infections and cancer cells. During chronic infection or tumor development, however, loss of function of T cells prevents ef..

TRANSCRIPTIONAL AND METABOLIC REGULATION OF EFFECTOR AND MEMORY LYMPHOCYTE DIFFERENTIATION

I am an internationally recognized expert in the field of lymphocyte biology. My work has shed light on antibody production, T cell response..

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

We thank Jeffrey Rathmell for providing us with Gls1 floxed mice. This work was funded by the National Health and Medical Research Council (NHMRC, project grant 1085151 and fellowship 1139607 to A.K., fellowship 1194779 to DTU, ideas grant 2003942 to S.G., fellowship 1154540 to M.J.M.) , the SwissNational Science Foundation (fellowship P300PB_177934 to P.M.G.) , and the Novartis Foundation for Medical-Biological Research (fellowships to S.S.G. and P.M.G.) . We acknowledge the Melbourne Cytometry Platform for provision of flow cytometry services and the NIH Tetramer Facility for providing tetramers. The graphical abstract was made using BioRender.com .r National Science Foundation (fellowship P300PB_177934 to P.M.G.) , and the Novartis Foundation for Medical-Biological Research (fellowships to S.S.G. and P.M.G.) . We acknowledge the Melbourne Cytometry Platform for provi-sion of flow cytometry services and the NIH Tetramer Facility for providing tet-ramers. The graphical abstract was made using BioRender.com .