Tumor-Associated Neutrophils Suppress Protumoral Il-17+Gamma Delta T Cells Through Induction Of Oxidative Stress

Interleukin 17 (IL-17)-producing gamma delta T cells (gamma delta 17T 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(-) V gamma 6(+) 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(-) 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(-)- gamma y6(+)gamma delta 117 T-cell proliferation in vivo. Moreover, human delta 5 (+)gamma delta 5 T cells, which contain most gamma delta 51 7T 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 177 T-cell axis in the tumor microenvironment.