Research Project
9516815
PROJECT SUMMARY/ABSTRACT: An essential step in an immune response against cancer is the presentation of tumor antigen to T cells by antigen presenting cells (APCs). Despite recent advances in immunotherapy, an effective method for stimulating the presentation of antigen by APCs has not been developed. Without new approaches that can either deliver antigen to APCs or activate APCs directly, cancer immunotherapy will continue to be limited to a small percentage of patients. The long-term goal of this research is to enhance tumor antigen presentation, which combined with current immunotherapeutic therapies, could create a robust immune response in cancer patients. In support of this goal, our lab has recently developed the first liposome delivery system (C3- liposomes) that can target all three APCs: dendritic cells, macrophages and B cells (Francian, 2017). Furthermore, preliminary results show that C3-liposomes deliver tumor antigen to APCs, leading to T cell activation and reduced tumor growth in a murine cancer model. Three independent strategies have been identified for improving tumor antigen presentation using C3-liposomes that will be pursued with the following three specific aims: Aim 1: Deliver tumor antigen encapsulated within C3-liposomes in a murine cancer model. Based on preliminary results showing reduced tumor growth with in vivo treatment, C3-liposomes will be used to deliver antigen to tumor bearing mice. C3-Liposomes are internalized into APC by the complement C3 receptor, closely mimicking how an actual pathogen would be processed for antigen presentation. Aim 2: Target CpG encapsulated within C3-liposomes to stimulate APC presentation. Toll-like receptor agonist, CpG, has a potent stimulatory effect on APCs and can overcome immunosuppressive cytokines released by the tumors. Delivery of CpG has the advantage of being applicable to all cancers, regardless of an identified tumor antigen, since it focuses on a general APC stimulation. Aim 3: Deliver mRNA coding for tumor antigen to APCs using cationic C3-liposomes. Delivery of mRNA to APC cell cytoplasm leads to presentation of tumor antigen by MHC-I instead of MHC-II. This has been shown to provoke a profound cytotoxic T cell response and has the added advantage of being more versatile and cost effective than encapsulating protein. The proposed aims would investigate three strategies to enhance antigen presentation, each of which has its own advantages and disadvantages. Completion of the research would indicate the most compelling use of C3-liposomes to increase antigen presentation in cancer patients. In addition, this study will build capacity for biomedical research, provide resources for undergraduates and greatly enhance the biomedical program at UAA. Ultimately, C3-liposomes could improve tumor antigen delivery and when used in combination with current immunotherapy could increase the percentage of patients who respond to therapy.
