The ability of cancer cells to invade and disseminate can be affected by components of the surrounding microenvironment. To identify dermal components that regulate the growth of epidermal carcinomas, we studied the genetic disease called xeroderma pigmentosum that bears mutations in genes involved in the nucleotide excision repair of DNA. Patients with xeroderma pigmentosum are more prone to develop cutaneous tumors than the general population and their dermal fibroblasts display the features of dermal cancer–associated fibroblasts, which promote the invasion of keratinocytes. Here, we report that 3-dimensional dermal cultures of fibroblasts from healthy donors but not from patients with xeroderma pigmentosum complementation group C express CLEC2A, which is the ligand of the activating NK cell receptor NKp65. A similar loss of CLEC2A was observed in sporadic dermal cancer–associated fibroblasts and upon the culture of fibroblasts with cutaneous squamous cell carcinoma–conditioned medium. Using an innovative 3-dimensional organotypic skin culture model that contain NK cells in addition to fibroblasts and squamous cell carcinoma cells, we unveiled a key role of CLEC2A that orchestrates a crosstalk between fibroblasts and NK cells, thereby leading to the control of squamous cell carcinoma invasion. These findings indicate that CLEC2A-expressing dermal fibroblasts play a major role in immune surveillance of the skin.

癌细胞入侵和扩散的能力可能会受到周围微环境成分的影响。为了确定调节表皮癌生长的真皮成分，我们研究了一种名为干性色素干燥症的遗传病，该病在涉及DNA核苷酸切除修复的基因中带有突变。色素干性皮肤病患者比一般人群更容易发生皮肤肿瘤，他们的皮肤成纤维细胞表现出与皮肤癌相关的成纤维细胞的特征，从而促进角质形成细胞的侵袭。在这里，我们报道了来自健康供体的成纤维细胞的3D真皮培养物，而不是来自干皮色素补充组C的患者的成纤维细胞的3D真皮培养物表达CLEC2A，CLEC2A是激活性NK细胞受体NKp65的配体。在散发性皮肤癌相关的成纤维细胞中以及在皮肤鳞状细胞癌条件培养基中培养成纤维细胞时，也观察到类似的CLEC2A丢失。我们使用一种创新的3维器官型皮肤培养模型，该模型除了包含成纤维细胞和鳞状细胞癌细胞外，还包含NK细胞，从而揭示了CLEC2A的关键作用，它可以协调成纤维细胞和NK细胞之间的串扰，从而控制鳞状细胞癌。入侵。这些发现表明表达CLEC2A的真皮成纤维细胞在皮肤的免疫监视中起主要作用。我们使用一种创新的3维器官型皮肤培养模型，该模型除了包含成纤维细胞和鳞状细胞癌细胞外，还包含NK细胞，从而揭示了CLEC2A的关键作用，它可以协调成纤维细胞和NK细胞之间的串扰，从而控制鳞状细胞癌。入侵。这些发现表明表达CLEC2A的真皮成纤维细胞在皮肤的免疫监视中起主要作用。我们使用一种创新的3维器官型皮肤培养模型，该模型除了包含成纤维细胞和鳞状细胞癌细胞外，还包含NK细胞，从而揭示了CLEC2A的关键作用，它可以协调成纤维细胞和NK细胞之间的串扰，从而控制鳞状细胞癌。入侵。这些发现表明表达CLEC2A的真皮成纤维细胞在皮肤的免疫监视中起主要作用。