Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells.
J Clin Invest
; 130(7): 3865-3884, 2020 07 01.
Article
em En
| MEDLINE
| ID: mdl-32324593
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.
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Base de dados:
MEDLINE
Assunto principal:
Microambiente Tumoral
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Células Supressoras Mieloides
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Imunidade Celular
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Macrófagos
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Neoplasias Experimentais
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article