期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 7, 页码 3865-3884出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI131859
关键词
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资金
- NIH [R01CA229451, R01HL141490, R01AI077610, R01CA226765, P41EB028239]
- Cancer Center Core grant [P30CA006973]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy funds
- Under Armour Women's Health and Breast Cancer Innovation grants
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 inflammatorytumor-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.
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