Early anti-tumor activity of oral Langerhans cells is compromised by a carcinogen. Early anti-tumor activity of oral Langerhans cells is compromised by a carcinogen

Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here we define the Langerhans cells (LC) of the tongue and demonstrate that LC protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and NK cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies while dendritic cells (DC), macrophages, and plasmacytoid DC (pDC) populate the epithelium. Single-cell RNAseq analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDC and precedes the formation of visible tumors. This suggests LC play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis. Overall design: The mice were treated with the carcinogen 4NQO in the drinking water to induce carcinogenesis in the tongue epithelium, the scRNAseq analysis was performed on cells purified from the tongue epithelium after enrichment to CD45+ cells.

口腔鳞状细胞癌（oral squamous cell carcinoma, OSCC）的早期诊断仍是尚未满足的临床需求。因此，阐明肿瘤发生前口腔鳞状细胞癌的初始事件，或可改善OSCC的预后。本研究明确了舌部朗格汉斯细胞（Langerhans cells, LC）的特征，并证实朗格汉斯细胞可通过快速激活能够清除γH2AX+上皮细胞的αβT细胞，从而保护上皮免受致癌物诱导的OSCC侵袭，而γδT细胞与自然杀伤（natural killer, NK）细胞则无此保护作用。然而，致癌物会扰乱上皮驻留单核吞噬细胞的稳态：在树突状细胞（dendritic cells, DC）、巨噬细胞及浆细胞样树突状细胞（plasmacytoid DC, pDC）浸润上皮组织的同时，朗格汉斯细胞的频率显著降低。单细胞RNA测序（single-cell RNAseq, scRNAseq）分析显示，这些新分化的细胞呈现免疫抑制表型，并伴随调节性T细胞（T regulatory cells, Treg）的扩增。调节性T细胞的聚集部分受浆细胞样树突状细胞调控，且发生于肉眼可见肿瘤形成之前。上述结果表明，朗格汉斯细胞在OSCC发生早期发挥保护性作用，而致癌物对单核吞噬细胞分化的扰乱则可促进口腔癌变进程。整体实验设计：通过饮水给小鼠施用致癌物4NQO，以诱导舌部上皮发生癌变；随后从舌部上皮中纯化富集CD45+细胞，并对其进行单细胞RNA测序分析。