Many factors limit the adaptive immune system from killing tumors; tumors and the resident inflammatory cells have numerous ways of inhibiting productive B and T cell responses. In addition, most antigens on tumors are “self antigens” not “neoantigens” or mutated proteins that lead to tumor development. Therefore immune cells bind weakly to tumors and respond weakly. Poor responses to tumor/self antigens seem disadvantageous, but actually this protects us from other autoimmune issues. If the immune system could be better stimulated when encountering tumors, it might mediate more effective responses against the tumor. Our goal is to make this happen.
Using an animal model for colon cancer, we are determining what substitutions in tumor antigen peptides improve antitumor immunity. These so-called “mimotope” peptides (mimics of epitopes) activate T cells that respond to the tumor more effectively than the natural tumor antigen. To understand how mimotope peptides affect T cell responses against tumors, we are characterizing the T cells responding to these peptides. In this system, we have also started studying inflammatory monocytes and the effect of the tumor vurses peripheral expression on antitumor T cell function. Finally, we are curious to know how the epigenome of tumor-specific T cells changes in response to effective vaccines and to the tumor.
We have a collaborative DoD-supported project with the labs of Drs. John Kappler (National Jewish), Peter Lee (City of Hope), and Paul Spellman (OHSU). This multi-team project combines genomics and immunotherapy to develop a new generation of therapeutic breast cancer vaccines, which improve the immune response against breast cancer. We are working on identifying the cognate antigens and mimotopes of breast cancer infiltrating T cells by using the T cells directly out of the tumors.