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
Affiliations
Patrick M. Gubser
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
Sharanya Wijesinghe
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
Leonie Heyden
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
Sarah S. Gabriel
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
David P. de Souza
Metabolomics Australia, Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia
Christoph Hess
Department of Biomedicine, Immunobiology, University of Basel and University Hospital of Basel, 4031 Basel, Switzerland; Department of Medicine, CITIID, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
Malcolm M. McConville
Metabolomics Australia, Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia
Daniel T. Utzschneider
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
Axel Kallies
The Peter Doherty Institute for Infection and Immunity and Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia; Corresponding author
Summary: 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 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
