Rapid dissemination of RET-transgene-driven melanoma in the presence of non-obese diabetic alleles: Critical roles of Dectin-1 and Nitric-oxide synthase type 2

Abstract

Mice transgenic for the RET oncogene provide a remarkable model for investigating the mechanisms underlying the promotion and the development of melanoma. This model was established on the C57BL/ 6 genetic background. In the present study, we investigated an effect of the strongly proinflammatory and autoimmune genetic makeup of the non-obese diabetic (NOD) strain. We bred (NODxB6)F1 mice and backcrossed them with NOD mice. F1 mice and mice at subsequent generations of backcrossing showed marked acceleration of tumor development, in particular with a more frequent and earlier extension of the primary uveal melanoma. In close relation with this severe evolution, we observed a profound drop in Dectin-1 expression on CD11b C Ly6GC granulocytic myeloid cells correlating with an expansion of CD4 C Foxp3 C T regulatory cell and of interferon(IFN)g-producing CD8 C T cell subsets in tumors. IFNg is a major inducer of the type 2 nitric-oxide synthase (Nos2) gene whose products are known to be tumorigenic. Germline inactivation of the Nos2 gene was associated with a dramatically improved tumor prognosis and a restoration of Dectin-1 expression on myeloid cells. Moreover, in vivo treatment of (NODxB6)F1.RET C mice with curdlan, a glucose polymer that binds Dectin-1, prevented tumor extension and was associated with marked reduction of the CD4 C Foxp3C T cell subset. These observations highlight the (NODxB6)F1.RET C mice as a new model to investigate the role of the immune system in the hosttumor relationship and point to Dectin-1 and Nos2 as potentially promising therapeutic targets.

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

“…In Ret mice with a NOD genetic background, we have shown that the rapid tumor cell dissemination strongly correlates with a reduced dectin-1 expression on myeloid cells that is prevented by NOS2 inactivation. 24 Here, we observed that RetNos2KO mice with C57Bl/6J genetic background survived better than Ret mice owing to the significant delay of tumor cell dissemination, despite a comparable primary tumor incidence in 6-mo-old animals. Our previous demonstration supported the key contribution of PMN-MDSCs in tumor cell dissemination in the Ret model.…”

The biology of uveal melanoma

“…IFN-γ-inducible nitric oxide synthase (Nos2) was involved in inflammation and accelerated tumorigenesis. These data point to a role of inflammation in UM development and to dectin-1 and Nos2 as potential therapeutic targets [395]. …”

The role of nitric oxide in melanoma

“…MDSCs inhibit T-cell function in melanoma both at the tumor itself and peripheral lymphoid organs [49]. In the RET (REearranged during Transfection) transgenic murine melanoma model, NOS2 expression was associated with increased MDSC recruitment by IL-12 producing γδ T cells and activation of T regulatory cells [57, 58]. VEGF secretion in the tumor microenvironment via iNOS dependent mechanisms also led to the recruitment of MDSC [59].…”