Role of cutaneous dendritic cells in skin cancer

Dendritic cells are specialized antigen presenting cells that are crucial for the induction of immunity and tolerance. The unique features of dendritic cells are the uptake, processing and presentation of antigens to nave T cells in lymphatic tissue. The activated T cells home to peripheral tissue, such as the skin, where they kill microbes and infected cells. The skin harbours two major subsets of dendritic cells, the Langerhans cells in the epidermis and the dermal dendritic cells in the dermis. In the event of infection, dendritic cells migrate from the skin to the draining lymph nodes where they activate T cells. Dendritic cells are widely used for immunotherapy of various tumors and have proven to be safe for the patients and to induce cytotoxic T cell responses against the tumor. The preparation of the dendritic cell vaccine is cumbersome and efficiency has to be improved since very few patients show partial or complete remission. We have further developed a novel strategy for immunotherapy against cancer, called epicutaneous immunization. This approach permits to vaccinate through the skin with the ultimate goal to load the patients` resident skin dendritic cells with antigen which then, in turn, induce an anti-tumor response. Preliminary results are promising in that we could initiate the development of long-lived cytotoxic T cell responses and inhibition of tumor growth. Langerhans cells so far were thought to be major players in skin immunity, however, in the last few years doubts were raised about their importance in vivo. Little is known about the role of dermal dendritic cells and the recent discovery of a third population of skin DC, shows how complex the skin immune system is. Although we know from our own work that Langerhans cells are very potent antigen-presenting cells and are crucial for the induction of T cell responses, the role of skin dendritic cells in immune responses against cutaneous tumors remains elusive. In this research proposal we will investigate the following aspects: (1) the specific role of cutaneous dendritic cells in skin cancer; (2) design novel improved immunization strategies by exploiting the immunotherapeutical potential of skin dendritic cells. This work is important because we need to understand the skin immune system to optimally harness the unique immunogenic properties of skin dendritic cells to treat cancer.

Dendritic cells are immune cells that initiate immune responses during infection and cancer. They continuously check the environment for invading pathogens or transformed tumor cells and after incorporating them, they migrate to the draining lymph nodes. There they present small pieces of the ingested material to other immune cells, the T cells, which become activated and, as effector cells, fight against pathogens or cancer cells. The focus of our work are the dendritic cells of the skin and their functional role in the induction of immune responses against skin cancer. It is essential to fully understand the functional role of skin dendritic cells in cancer to harness their potential for immunotherapy. This knowledge will allow to develop novel and improved immunotherapies for cancer patients. In our project we aimed to investigate the role of skin dendritic cells in melanoma and non-melanoma skin cancer, such as squamous cell carcinoma. For this purpose we used mice that develop melanoma within 4-6 months of age due to genetic abberation. Through the investigation of tumor-bearing mice we now understand how the tumor affects the immune status of these tumor mice. This situation is comparable to what happens in cancer patients. Effector T cells which should fight against the tumor, were compromised in their function by the recruitment of suppressive immune cells. Moreover, we observed a loss of skin dendritic cells from tumor microenvironment, and the few remaining cells were functionally impaired. These findings were confirmed in experiments, in which we specifically depleted various skin dendritic cell subsets. In a model for squamous cell carincoma, in which tumors are induced by repeated application of chemicals on the skin, we had similiar findings in that skin dendritic cells were important for the recruitment of effector cells into the tissue. The importance of skin dendritic cells in an immune response against the tumor was confirmed by the observation that in their absence tumors developed in an accelerated way. From the findings of our work we can conclude that skin dendritic cells are crucial for the induction of tumor immunity. Their loss or functional impairment, as induced by tumors, allows tumors to evade immune recognition and grow progressively. The next goal is to manipulate the skin immune system to restore the functional properties of skin dendritic cells in cancer.