Institute of Biomedical and Oral Research, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Department of Oral and Maxillofacial Surgery, Rambam Medical Care Center, Jerusalem 3109601, Israel.
Proc Natl Acad Sci U S A. 2022 Jan 18;119(3). doi: 10.1073/pnas.2118424119.
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 (LCs) of the tongue and demonstrate that LCs protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX epithelial cells, whereas γδT and natural killer cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies, while dendritic cells (DCs), macrophages, and plasmacytoid DCs (pDCs) populate the epithelium. Single-cell RNA-sequencing 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 pDCs and precedes the formation of visible tumors. This suggests LCs play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.
早期诊断口腔鳞状细胞癌（OSCC）仍然是一个未满足的临床需求。因此，阐明肿瘤发生前 OSCC 的初始事件可能有利于 OSCC 的预后。在这里，我们定义了舌头上的朗格汉斯细胞（LCs），并证明 LCs 通过快速激活能够清除 γH2AX 上皮细胞的 αβT 细胞来保护上皮免受致癌物诱导的 OSCC，而 γδT 和自然杀伤细胞则是可有可无的。然而，致癌物会使上皮固有单核吞噬细胞失调，降低 LCs 的频率，同时树突状细胞（DCs）、巨噬细胞和浆细胞样树突状细胞（pDCs）在上皮中定植。单细胞 RNA 测序分析表明，这些新分化的细胞表现出免疫抑制表型，并伴有 T 调节（Treg）细胞的扩增。Treg 细胞的积累部分受到 pDCs 的调节，并且发生在可见肿瘤形成之前。这表明 LCs 在 OSCC 发生的早期具有保护作用，但致癌物对单核吞噬细胞分化的失调促进了口腔癌的发生。
