Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma.
γδ T lymphocytes may exert either protective or tumor-promoting functions in cancer, mostly based on their polarization toward interferon (IFN)-γ or interleukin (IL)-17 productions, respectively. Here, we demonstrate that γδ T cells accelerate the spontaneous metastatic melanoma development in a model of transgenic mice for the human RET oncogene (Ret mice). We identify unanticipated roles of inducible nitric oxide synthase (NOS2) in favoring the recruitment of pro-tumor γδ T cells within the primary tumor. γδ T cells isolated from Ret mice deficient for NOS2 produced more IFNγ and less IL-17 than their counterparts from Ret mice. By supporting IL-17 production by γδ T cells, NOS2 leads to the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and metastasis formation. NOS2 also reduces the cytotoxicity of γδ T cells toward melanoma cells. Finally, we detected NOS2 expressing γδ T cells in the primary tumor and tumor-draining lymph nodes in Ret mice, but also in human melanoma. Overall our results support that this NOS2 autocrine expression is responsible for the polarization of γδ T cells toward a pro-tumor profile.
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Laetitia
L
Douguet
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Lloyd
L
Bod
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Renée
R
Lengagne
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Ecole Normale Supérieure, Cachan, France.
Laura
L
Labarthe
Nagoya University Graduate School of Medicine , Nagoya, Aichi, Japan.
Masashi
M
Kato
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Cochin Hospital, Paris, France.
Marie-Françoise
MF
Avril
Institut National de la Santé et de la Recherche Médicale (INSERM), U1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Armelle
A
Prévost-Blondel
Interleukin 17; NOS2; melanoma; pro-tumor functions; γδ T cells