Tolerogenic IDO1+CD83- Langerhans Cells in Sentinel Lymph Nodes of Patients with Melanoma

Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin(+) LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1(-)CD83(+) LCs; real immature IDO1(-)CD83(-) LCs; tolerogenic mature IDO1(+)CD83(+) LCs; tolerogenic immature IDO1(+)CD83(-) LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR <= 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma.

Automated summary

Langerhans cells (LCs) are important regulators of anti-cancer immune responses, but cancer can alter their functions, leading to immune tolerance. In this study, IDO1 expression was investigated in LCs from sentinel lymph nodes (SLNs) of melanoma patients. The results showed that a subset of Langerin(+) LCs in the T cell-rich area of SLNs expressed IDO1. The expression of IDO1 did not significantly differ between SLNs with or without metastases, but was higher in SLN LCs of patients with mitotic rate > 1 in primary melanoma. Immature SLN LCs could be induced to mature after in vitro stimulation by inflammatory cytokines. These findings provide new insights for immunotherapy targeting LCs in melanoma patients.