The majority of cancer patients do not yet benefit from immunotherapy, including from immune checkpoint therapies that invigorate the patients’ own immune systems to fight their tumors. In many cases the underlying reason is that tumors are not recognized strongly enough by the patients’ immune systems and consequently, are only poorly infiltrated by anti-tumor effector T cells that could otherwise reject the tumor. In addition, so-called regulatory T cells (Treg) actively limit the anti-tumor activity of those effector T cells that manage to enter the tumor tissue. One approach to address this situation has been to deplete Treg. However, effective depletion of these cells may cause autoimmune disease, because Treg also prevent our immune system from turning against our healthy tissues.

We have discovered a method to selectively reprogram immunosuppressive Treg in tumor tissue, but not those in healthy tissues, and convert them from immuno-suppressive pro-tumor into inflammation-causing anti-tumor effector cells. Thereby, we are able to sensitize otherwise treatment-resistant mouse tumors to immune checkpoint therapy and cause their rejection. This finding suggests a potential new strategy to successfully treat many of those cancer patients who currently do not respond to immunotherapy. However, in order to develop this method for human therapy we will need to understand 1) why only Treg in tumor tissue are reprogrammed, 2) through what mechanism Treg are induced to produce inflammatory cytokines, and 3) if human Treg can be reprogrammed the same way as mouse Tregs. We propose to address these questions in this project.