Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
Year: 2020
Type: article
Abstract: Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a 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 as 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 antitumor 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.
DOI: 10.1172/jci131859
Authors: Min-Hee Oh, Im-Hong Sun, Liang Zhao, Robert D. Leone, Im-Meng Sun, Wei Xu, Samuel L. Collins, Ada J. Tam, Richard L. Blosser, Chirag H. Patel, Judson M. Englert, Matthew L. Arwood, Jiayu Wen, Yee Chan-Li, Lukáš Tenora, Pavel Majer, Rana Rais, Barbara S. Slusher, Maureen R. Horton, Jonathan D. Powell
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: Johns Hopkins University, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Awards: G1165598027, Zeiss LSM780 Confocal Microscope for a Core Facility, G17818401, G20398883, A central role for mTOR in Determining T Cell Activation versus Tolerance, G3005178836, G3270900219, Cell-targeted glutamine antagonists as a novel therapy for lymphoma, G4345342120, G4513878175, G465951118, G5469559864, Targeting Tumor Metabolism as a Means of Enhancing Immunotherapy, G6065882732, G8978593438, G9000025451, G9000025631, G9000041231
OpenAlex ID: W3020598614