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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.

Original publication

DOI

10.1371/journal.pbio.2004990

Type

Journal article

Journal

PLoS biology

Publication Date

05/2018

Volume

16

Addresses

Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Keywords

Neutrophils, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Humans, Liver Neoplasms, Experimental, Reactive Oxygen Species, Glutathione, Cell Proliferation, Oxidative Stress, Male, Intraepithelial Lymphocytes