Tumor-associated neutrophils suppress pro-tumoral IL-17+ [gamma][delta] T cells through induction of oxidative stress

Interleukin 17 (IL-17)-producing [gamma][delta] T cells ([gamma][delta]17 T cells) have been recently found to promote tumor growth and metastasis formation. How such [gamma][delta]17 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 [gamma][delta]17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27.sup.- V[gamma]6.sup.+ [gamma][delta]17 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.sup.- [gamma][delta]17 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.sup.- V[gamma]6.sup.+ [gamma][delta]17 T-cell proliferation in vivo. Moreover, human V[delta]1.sup.+ [gamma][delta] T cells, which contain most [gamma][delta]17 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/[gamma][delta]17 T-cell axis in the tumor microenvironment.