Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
- Oh, Min-Hee
- Sun, Im-Hong
- Zhao, Liang
- Leone, Robert D.
- Sun, Im-Meng
- Xu, Wei
- Collins, Samuel L.
- Tam, Ada J.
- Blosser, Richard L.
- Patel, Chirag H.
- Englert, Judson M.
- Arwood, Matthew L.
- Wen, Jiayu
- Chan-Li, Yee
- Tenora, Lukáš
- Majer, Pavel
- Rais, Rana
- Slusher, Barbara S.
- Horton, Maureen R.
- Powell, Jonathan D.
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.