Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis

Erika M. Palmieri, Alessio Menga, Rosa Martín-Pérez, Annamaria Quinto, Carla Riera-Domingo, Giacoma De Tullio, Douglas C. Hooper, Wouter H. Lamers, Bart Ghesquière, Daniel W. McVicar, Attilio Guarini, Massimiliano Mazzone, Alessandra Castegna

Research output: Contribution to journalArticlepeer-review

Abstract

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.

Original languageEnglish
Pages (from-to)1654-1666
Number of pages13
JournalCell Reports
Volume20
Issue number7
DOIs
Publication statusPublished - Aug 15 2017

Keywords

  • glutamine
  • glutamine synthetase
  • HIF1α
  • IL-10
  • macrophages
  • metabolic rewiring
  • metastasis
  • starvation
  • succinate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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