Grant: Project Grant

Cancer immunotherapy is a revolutionary approach based on methods that stimulate the immune responses in our body to kill the cancer cells. Immune cells called cytotoxic T lymphocytes (CTLs) specifically recognize cancer cells to eliminate them. However, when a tumor is established, cancer cells use several mechanisms that dampen the immune system. Growing tumors establish an immunosuppressive microenvironment that renders CTLs dysfunctional. Tumors can also escape from immune recognition by decreasing the expression of proteins on their cell surface called major histocompatibility complex I (MHC-I). MHC-I proteins can be increased on tumor cells by delivering NLRC5, a master protein that promotes the expression of MHC-I and thereby increases tumor cell visibility to the CTLs. While most ovarian cancer patients do not respond to existing immunotherapies, we have made the remarkable discovery that delivering NLRC5 to ovarian tumors in mice renders them more responsive to immunotherapies, generating long-term survivors. We propose to explore further how NLRC5 sensitizes the cancer cells to those treatments. We will also develop a viral platform that can more stably deliver NLRC5 to ovarian tumors, including fresh tumors removed from ovarian cancer patients, and test its ability to stimulate the activation of antitumoral CTLs. Focusing on ovarian cancer, a cancer that is in dire need of more effective treatments, we anticipate that this approach should result in a treatment or combination of treatments that boost the killing capacities of CTLs and stimulate the formation of memory that will confer long-lasting protection against relapse.