Virus-induced Tumor MHC Ligandome Discovery for Cancer Immunotherapy

One of the most promising modern-age cancer treatment options is cancer immunotherapy. It uses the immune system, in particular T cells, to attack existing and reoccurring cancer cells. Many studies so far have shown that this T cell-based anti-tumor immunity increases patient survival. Thus, understanding the activation and role of these anti-tumor T cells is important in generating novel immunotherapies with enhanced capacity to fight cancer. Anti-tumor T cells identify and kill cancer cells when they recognize tumor peptide ligands bound to Major Histocompatibility Complex (MHC) molecules on the cell surface. Since cancers exhibit proteins with mutations or abnormal expression, they possess a Tumor MHC Ligandome (TML) that is unique compared to "normal" tissues. These TMLs can thus be used to design immunotherapeutics (e.g., T cell vaccines) that promote anti-tumor immunity. Unfortunately, the identification of TMLs has remained challenging mainly due to two reasons. First, tumors have many mechanisms to escape detection by the immune system, such as decreased MHC expression. Second, the precise identification of MHC ligands has been difficult due to technological limitations. Here, we propose an innovative approach that addresses these challenges. We will use reovirus, known for its direct cancer-killing abilities, to overturn impaired TML presentation. Reovirus will promote the display of otherwise inaccessible tumor peptides, resulting in unique virus-driven TMLs. Next, we will use cutting-edge technological advances in mass spectrometry, combined with next generation exome sequencing, to identify TMLs. Ultimately, we aim to determine immune targets that can be used to promote anti-tumor T cell responses. We will apply this knowledge to design immunotherapies that will improve prevention, prognosis, or therapy for various cancers.