Grant: Project Grant

Activating or dampening immune responses are events that are triggered by the binding of co-stimulatory and co-inhibitory molecular partners expressed on T cells, antigen-presenting cells and cancer cells. The uncontrolled activation of immune responses can manifest itself as inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and Crohn's disease. In contrast, the suppression of immune responses directed at tumor cells reflects the fact that such cells are perceived as being normal cells by presenting a complement of "self antigens", allowing cancer cells to growth in an uncontrolled fashion. Altering the interaction of co-inhibitory molecules with their respective ligands [immune checkpoint pairs such as PD-1:PD-L1 and CD200:CD200R1] can be used to re-tune immune responses. For instance, clinical trials have recently demonstrated that blocking the binding of PD-1 to PD-L1 with either anti-PD-1 or anti-PD-L1 antibodies represents a powerful way of restoring immune responses for treating late stage patients with melanoma and other cancers. Dampening inflammatory responses can also be achieved by using for instance CD200Fc or agonists of its receptor CD200R1 present on immune cells. We have found that VISTA, a newly identified immune checkpoint regulator, can be engineered to act as a powerful anti-inflammatory agent. Here, we propose to identify VISTA's receptor on T cells and cancer cells. Another aim is to evaluate the anti-inflammatory properties of our designed VISTA homolog in several mouse models of inflammation. Finally, we also plan to generate VISTA blockers that will be evaluated in tumor models as agents able to restore immune responses against tumor cells. This proposal will open-up a new area of research in immunotherapy leading to tailored VISTA-blocking agents to treat cancer patients as well as VISTA-like molecules to reduce inflammatory responses in patients with acute and chronic inflammatory diseases.