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

Grant support

The Francis Crick Institute (grant number FC001129). Received by MI and VP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. European Research Council (grant number CoG_646701). Received by BSS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Fundação para a Ciência e Tecnologia (grant number IF/00004/2014). Received by KS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Fundação para a Ciência e Tecnologia (grant number PD/BD/114099/2015). Received by SM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was supported by the European Union’s Horizon 2020 research and innovation programme under Twinning grant agreement No 692022 (TwinnToInfect). Received by iMM. This work was also kindly backed by the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu). COST is supported by the EU Framework Program Horizon 2020. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.