Immunotherapy of cancer with Langerin-ligand liposomes

Dendritic cells residing in the skin act as sentinels of the immune system by recognizing invading pathogens and growing tumors. They take up proteins from pathogens and tumors and after migration to the draining lymph nodes induce an immune response. These proteins, also called antigens, are cut into smaller pieces, and these peptides are presented on the surface of dendritic cells to T cells, the effector cells of the immune system. This antigen presentation process occurs in the draining lymph node and leads to the proliferation and activation of T cells. Thereafter, activated T cells infiltrate the affected skin area to destroy infected and tumor cells. This unique ability renders dendritic cells optimal targets for immunotherapy of cancer. Indeed, dendritic cell-based immunotherapy has proven its potential to prime T cell responses against tumor antigen, however clinical responses need further improvement. To arm dendritic cells for induction of tumor immunity, they need to be loaded with tumor antigens followed by strong activation so that they optimally interact with T cells. These antigens can be delivered to dendritic cells in manifold ways, such as by conjugating them to antibodies that bind to the surface of dendritic cells, which is currently tested in the clinics. Another approach involves packaging the tumor antigens in nanoparticles. Together with a research collaborator, we have developed such a delivery system to specifically target a subtype of dendritic cells in the skin, namely the Langerhans cells residing in the outermost layer of the skin, the epidermis. We will use nanoparticles coated with a ligand specific for the cell surface molecule Langerin that is uniquely expressed by Langerhans cells. These nanoparticles will ensure that encapsulated antigens are delivered to Langerhans cells for subsequent antigen presentation to T cells in draining lymph nodes. In our project, we hypothesize that antigens targeted with this specific Langerin-ligand to Langerhans cells will induce T cell responses that are able to fight melanoma, the most dangerous skin cancer type. In our project, we will investigate how Langerhans cells are optimally loaded with nanoparticles, which tumor antigens are the most efficient ones, how the T cells are optimally activated and which immunization route is the best, e.g. intradermal injection of vaccines or topical application to the skin after laser pretreatment to break the skin barrier. The overall goal of our project is to develop a novel Langerhans cell-based vaccine platform and test the efficiency of our approach for immunotherapy of melanoma.