Monocytes promote UV‐induced epidermal carcinogenesis

Mononuclear phagocytes consisting of monocytes, macrophages, and DCs play a complex role in tumor development by either promoting or restricting tumor growth. Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer arising from transformed epidermal keratinocytes. While present at high numbers, the role of tumor‐infiltrating and resident myeloid cells in the formation of cSCC is largely unknown. Using transgenic mice and depleting antibodies to eliminate specific myeloid cell types in the skin, we investigated the involvement of mononuclear phagocytes in the development of UV‐induced cSCC in K14‐HPV8‐E6 transgenic mice. Although resident Langerhans cells were enriched in the tumor, their contribution to tumor formation was negligible. Equally, dermal macrophages were dispensable for the development of cSCC. In contrast, mice lacking circulating monocytes were completely resistant to UV‐induced cSCC, indicating that monocytes promote tumor development. Collectively, these results demonstrate a critical role for classical monocytes in the initiation of skin cancer. Different subsets of mononuclear phagocytes accumulated in the tumor of a UV‐induced model of cutaneous squamous cell carcinoma (cSCC). While cSCC developed in the absence of Langerhans cells and dermal macrophages, mice lacking classical monocytes were completely protected from tumor formation, indicating a critical role for monocytes in tumor development.