NK cell and fibroblast-mediated regulation of skin squamous cell carcinoma invasion by CLEC2A is compromised in Xeroderma Pigmentosum

Abstract The ability of cancer cells to invade and disseminate can be affected by components of the surrounding microenvironment. To identify dermal components regulating the growth of epidermal carcinomas, we studied the xeroderma pigmentosum genetic disease that bears mutations in genes involved in nucleotide excision DNA repair. Xeroderma pigmentosum patients are more prone to develop cutaneous tumors compared to the general population and their dermal fibroblasts display features of dermal cancer-associated fibroblasts, promoting keratinocyte invasion. Here, we report that 3-dimensional dermal cultures of fibroblasts from healthy donors, but not from XP-C patients, express CLEC2A, the ligand of the activating Natural Killer cell receptor NKp65. A similar loss of CLEC2A was observed in sporadic dermal cancer-associated fibroblasts and upon culture of fibroblasts with cutaneous SCC-conditioned medium. Using an innovative 3-dimensional organotypic skin culture model that contain NK cells in addition to fibroblasts and SCC cells, we unveil a key role of CLEC2A that orchestrates a cross-talk between fibroblasts and NK cells leading to the control of SCC invasion. These findings indicate that CLEC2A-expressing dermal fibroblasts play a major role in skin immune surveillance.