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Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
Min-Hee Oh, … , Maureen R. Horton, Jonathan D. Powell
Min-Hee Oh, … , Maureen R. Horton, Jonathan D. Powell
Published April 23, 2020
Citation Information: J Clin Invest. 2020;130(7):3865-3884. https://doi.org/10.1172/JCI131859.
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Research Article Immunology Oncology Article has an altmetric score of 27

Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells

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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.

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

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Figure 10

Glutamine antagonism alters metabolism of metastatic sites in glutamine-dependent and -independent pathways.

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Glutamine antagonism alters metabolism of metastatic sites in glutamine-...
4T1 cells (1 × 105) were implanted subcutaneously into mammary fat pads of BALB/cJ female mice. 4T1 tumor–bearing mice were treated with JHU083 (1 mg/kg) starting on day 7 after tumor inoculation. After 7 days of treatment, a lower dose (0.3 mg/kg) of JHU083 was used. On day 17, whole lungs from mice were harvested, and whole lung lysates were analyzed by LC-MS. (A) Principal component (PC) analysis between the vehicle-treated (NT) (green) and JHU083-treated (pink) lungs and (B) heatmap visualization of the metabolite changes between NT (green) and JHU083-treated (red) groups is shown. (C) Venn diagram displaying shared significantly changed (1.5-fold, P < 0.05) metabolites from tumor and lung. (D) Relative amounts of kynurenine from tumor (left) and lung (right) between NT and JHU083-treated groups. Data are from 1 experiment with 4 to 5 mice per group and are presented as the mean ± SD. **P < 0.01; ****P < 0.001 by t test (B) or Mann-Whitney test (D).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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