Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy.
Department of Health Sciences, Section of Dermatology, University of Florence, 50125 Florence, Italy.
Int J Mol Sci. 2022 Mar 22;23(7):3441. doi: 10.3390/ijms23073441.
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.
朗格汉斯细胞（LCs）是抗肿瘤免疫反应的关键调节者。然而，癌症可以改变树突状细胞（DCs）的功能，导致免疫耐受。吲哚胺 2,3-双加氧酶（IDO1）在这个过程中起着至关重要的作用。在黑色素瘤患者的前哨淋巴结（SLN）中，LCs 表现出有利于耐受的表型和功能改变。在此，我们旨在研究黑色素瘤患者 SLN LCs 中的 IDO1 表达。通过免疫荧光分析，我们发现位于 SLN T 细胞丰富区的一部分 Langerin+LCs 表现出典型的树突状形态，并表达 IDO1。有或无转移的 SLN 之间 IDO 的表达没有显著差异。IDO1/CD83 双重染色鉴定了四个 LCs 亚群：真正成熟的 IDO1−CD83+ LCs；真正不成熟的 IDO1−CD83− LCs；耐受成熟的 IDO1+CD83+ LCs；耐受不成熟的 IDO1+CD83− LCs。与阴性 SLN 相比，转移性 SLN 中后一个亚群显著增加（p<0.05），与原发性黑色素瘤中有丝分裂率（MR）>1 的患者的 SLN LCs 相比，MR≤1 的患者也显著增加（p<0.05）。最后，不成熟的 SLN LCs 在体外受到炎症细胞因子的刺激后，通过 CD83 的上调获得了成熟的表型。这些结果为针对黑色素瘤患者体内 LC 的免疫治疗方法提供了新的思路。
