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

Sofia Mensurado,Karine Serre,Natacha Gonçalves-Sousa,Marie Malissen,Venizelos Papayannopoulos,Telma Lança,Bruno Silva-Santos,Hiroshi Kubo,Marianna Ioannou,Margarida Rei

doi:10.1371/journal.pbio.2004990

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.

Highlights

A hallmark of solid tumors is their infiltration by immune cells that can either inhibit or promote tumor cell growth
We unexpectedly found that IL17+ γδ T cells express very low levels of the antioxidant, glutathione, and are very sensitive
The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Summary

Introduction

A hallmark of solid tumors is their infiltration by immune cells that can either inhibit or promote tumor cell growth. Amongst such immune populations, γδ T cells are known to contribute to protective responses because of their potent ability to kill tumor cells and to produce cytokines like interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) [1,2,3,4,5], which constitutes a solid basis for γδ T-cell–based cancer immunotherapy strategies [6]. The Vδ1+ subpopulation of human γδ T cells was reported to be a major source of IL17 in colon cancer [13] and squamous cell skin cancer [14] patients and to promote inflammation-induced cancer progression [16]

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