Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
- 1 July 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (7), 3865-3884
- https://doi.org/10.1172/jci131859
Abstract
Myeloid cells comprise a major component of the tumor-microenvironment (TME) promoting tumor growth and immune evasion. By employing a novel small molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well immunogenic cell death leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid derived cells leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced anti-tumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.Keywords
Funding Information
- NIH Office of the Director (R01CA229451)
- NIH Office of the Director (S10 OD016374)
- NIH Office of the Director (R01HL141490)
- NIH Office of the Director (R01AI077610)
- NIH Office of the Director (R01CA226765)
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (N/A)
- Under Armour Women’s Health & Breast Cancer Innovation Grants (N/A)
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