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

0531033 - ÚOCHB 2021 RIV US eng J - Journal Article
Oh, M. H. - Sun, I. H. - Zhao, L. - Leone, R. D. - Sun, I. M. - Xu, W. - Collins, S. L. - Tam, A. J. - Blosser, R. L. - Patel, C. H. - Englert, J. M. - Arwood, M. L. - Wen, J. - Chan-Li, Y. - Tenora, Lukáš - Majer, Pavel - Rais, R. - Slusher, B. S. - Horton, M. R. - Powell, J. D.
Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells.
Journal of Clinical Investigation. Roč. 130, č. 7 (2020), s. 3865-3884. ISSN 0021-9738. E-ISSN 1558-8238
Institutional support: RVO:61388963
Keywords : cancer immunotherapy * immunology * innate immunity * oncology
OECD category: Medicinal chemistry
Impact factor: 14.808, year: 2020
Method of publishing: Open access
https://www.jci.org/articles/view/131859

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.
Permanent Link: http://hdl.handle.net/11104/0309795