Dendritic cells as bridge between innate and adaptive immunity in skin carcinogenesis

Due to their localization, cutaneous dendritic cells (DC) are the first antigen presenting cells that encounter emerging skin cancer cells. In the skin, Langerhans cells (LC) populate the epidermis the dermis harbours different types of dermal DC. Moreover, DC function as a brigde between innate and adaptive immunity, hence they are crucial for immunosurveillance of tumors. Their functional properties can be exploited to activate the immune system. However, their relative roles in immunosurveillance and induction of innate and adaptive immune responses to skin cancer are largely unknown. Non melanoma skin cancer (NMSC, e.g. squamous cell carcinoma (SCC) and basal cell carcinoma (BCC)) poses a main health problem with increasing prevalence and recurrence. So far few reports demonstrated that LC and myeloid DC are present and exert different functions in human SCC. From our previous work we know that LC are potent immune activators rendering them promising targets for immunotherapeutical interventions. In this project proposal we want to unravel the immunological events during chemical carcinogenesis that lead to the development of SCC. We have gathered preliminary data that suggest that cutaneous Langerin-positive DC/LC are required for immunosurveillance of chemically induced tumors in a mouse model. We aim to understand the specific roles of the various skin DC subsets during tumor initiation and progression. The specific questions we ask are: (1) Which functional roles do the various skin DC subsets exert during chemical initiation of SCC? (2) How is the immune system alerted to transformed epithelial cells? (3) How are immune cells functionally compromised in mice with established carcinoma? The expected findings will crucially add to our knowledge on the functional roles of skin DC in tumor immunity. The results from this project will point out possibilities how to successfully manipulate the immune system to overcome immunosupression in the tumor milieu. Future advancement of immunotherapeutical treatments for cancer will benefit from the data received from this study.

Ultraviolet radiation is the predominant cause of human skin cancer, albeit environmental exposure to chemicals can also lead to mutations driving tumor development. Non-melanoma skin cancer, such as squamous cell carcinoma, is a tumor of the keratinocytes, the cells building the outermost barrier of the skin, namely the epidermis. As the skin is constantly in contact with hazardous substances and ultraviolet radiation, immunosurveillance is important to detect cells with DNA-damage and to prevent cancer. Innate immune cells, such as natural killer cells, are known for their ability to recognize and clear DNA-damaged cells. In addition, cutaneous dendritic cells are the first antigen presenting cells that encounter emerging skin cancer cells. Since dendritic cells function as a bridge between innate and adaptive immunity, they have a crucial role in tumor immunity. The starting point of our project was to understanding how the innate immune system and DNA-damaged, transformed skin cells interact. To study this we chose a preclinical mouse model in which squamous cell carcinoma develops after repeated exposure to a topically applied carcinogen. Our project investigated the early immunological events occurring during chemical carcinogenesis. We focused on a special subtype of skin dendritic cells, the Langerhans cells, as they reside in the epidermis next to keratinocytes, which are mainly affected by chemical carcinogenesis. In our project, we unraveled that Langerhans cells are crucial for the elimination of transformed keratinocytes, and thus can inhibit chemical carcinogenesis. After topical application of the carcinogen, Langerhans cells released the proinflammatory cytokine TNF-alpha. Subsequently, TNF-alpha triggered the release of chemokines, which mediated the recruitment of natural killer cells to the affected epidermis. These recruited natural killer cells eliminated DNA-damaged skin cells and prevented tumor development. This collaboration of LC and NK cells in the prevention of carcinogen-induced skin cancer was hitherto unknown and might also be crucial for UV-triggered tumorigenesis, a topic we are currently investigating in our lab. It will also be important to study this interaction between dendritic cells and natural killer cells in other skin tumor entities, such as melanoma. In summary, we can say that our findings are helped to gai a better understanding of early immunological events during skin carcinogenesis, which might also help to advance immunotherapy for cancer.