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.
Journal of Clinical Investigation 130(7):p 3865-3884, July 2020. | DOI: 10.1172/JCI131859

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.

Copyright © 2020 The American Society for Clinical Investigation, Inc.