Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress

PLoS Biol. 2018 May 11;16(5):e2004990. doi: 10.1371/journal.pbio.2004990. eCollection 2018 May.

Abstract

Interleukin 17 (IL-17)-producing γδ T cells (γδ17 T cells) have been recently found to promote tumor growth and metastasis formation. How such γδ17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing γδ17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27- Vγ6+ γδ17 T cells via induction of oxidative stress, thereby preventing them from constituting the major source of pro-tumoral IL-17 in the tumor microenvironment. Mechanistically, we found that low expression of the antioxidant glutathione in CD27- γδ17 T cells renders them particularly susceptible to neutrophil-derived reactive oxygen species (ROS). Consistently, superoxide deficiency, or the administration of a glutathione precursor, rescued CD27- Vγ6+ γδ17 T-cell proliferation in vivo. Moreover, human Vδ1+ γδ T cells, which contain most γδ17 T cells found in cancer patients, also displayed low glutathione levels and were potently inhibited by ROS. This work thus identifies an unanticipated, immunosuppressive yet antitumoral, neutrophil/ROS/γδ17 T-cell axis in the tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Glutathione / metabolism
  • Humans
  • Intraepithelial Lymphocytes / physiology*
  • Liver Neoplasms, Experimental / immunology*
  • Male
  • Mice, Inbred C57BL
  • Neutrophils / physiology*
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Glutathione