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

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

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 11

Glutamine antagonism reduces IDO expression by decreasing p-STAT1/3 signaling.

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Glutamine antagonism reduces IDO expression by decreasing p-STAT1/3 sign...
(A–D) 4T1 cells (1 × 105) or 1 × 105 GFP+ 4T1 cells were implanted subcutaneously into mammary fat pads of BALB/cJ mice. MC38 cells (5 × 105) were implanted subcutaneously into the flank of C57BL/6J mice. Tumor-bearing mice were treated with JHU083. On day 21, IDO expression in tumor lysates from (A) 4T1 tumor– or (B) MC38 tumor–bearing mice was measured by immunoblot. On day 12, (C) GFP+ tumor cells, (D) TAMs, and MDSCs were sorted. Cells were lysed and IDO expression was measured by immunoblot. (E) The ratio of kynurenine to tryptophan in tumors. (F) 4T1 tumor cells were cultured in the presence or absence of DON (0.5 or 1 μM) and IFN-γ for 6 or 24 hours. p-STAT1 (Ser727) and IDO expression was measured by immunoblot (left). After 6 hours with 1 μM DON treatment, Ido mRNA levels were measured by q-PCR (right). (G) RAW264.7 cells were cultured in the presence or absence of DON (0.5 or 1 μM) and IFN-γ for 6 or 24 hours. p-STAT3 (Ser727) and IDO were measured by immunoblot (left). After 6 hours with 1 μM DON treatment, Ido mRNA levels were measured by q-PCR (right). (H) 4T1 tumor–bearing mice were treated with JHU083. On day 14, IDO expression within lung lysates from tumor-free and 4T1 tumor–bearing mice with or without JHU083 treatment was measured by immunoblotting. (I) Left: Heatmap visualization of P values from Pearson’s correlation analysis (non-log scale for calculation) using TCGA normal and breast-invasive carcinoma data between the glutamine-utilizing enzymes inhibited by DON and IDO expression. Right: Enzyme and IDO correlation data. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01; ****P < 0.001 by Mann-Whitney t test (E) or 1-way ANOVA with Tukey’s multiple-comparisons post hoc test (F and G).