The Achilles heel of pro-tumoral γδ ​T cells

Tumors are infiltrated by many immune cells that influence many aspects of cancer progression and outcome. Among tumor-infiltrating lymphocytes, γδ T cells play dual functions in the tumor milieu; whereas those that produce the antitumor cytokine interferon-γ are protective, their counterparts that make interleukin 17 (IL-17) support tumor growth. Here, the authors found that IL-17+ γδ T cells express very low levels of the antioxidant, glutathione, and are very sensitive to reactive oxygen species (ROS), thus revealing their Achilles' heel. Indeed, as ROS-producing neutrophils accumulate within tumors, they inhibit IL-17+ γδ T-cell proliferation and thereby suppress their pro-tumoral activities. This findings suggest that modulation of local levels of oxidative stress may have important therapeutic implications.

Authors and Affiliations:

Sofia Mensurado: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Margarida Reis: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Telma Lança: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Marianna Ioannou: The Francis Crick Institute, London, United Kingdom

Natacha Gonçalves-Sousa: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Hiroshi Kubo: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Marie Malissen: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, Inserm, CNRS, Marseille, France

Venizelos Papayannopoulos: The Francis Crick Institute, London, United Kingdom

Karine Serre: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Bruno Silva-Santos: Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal, Instituto Gulbenkian de Ciência, Oeiras, Portugal

Contributed equally to this work with: Karine Serre, Bruno Silva-Santos

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.

Journal: PloS Biology

Link: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2004990