The role of Toll-like receptor 3 in overcoming cancer immunoediting

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DESCRIPTION (provided by applicant): The long-term goal of this research is to develop immune modulators that activate a potent immune response leading to the elimination of human cancer cells. Cancer immunotherapy directs the power of the immune system to select for and eliminate tumor cells. In doing so, tumor variants that are not immediately removed battle with the immune system in a dynamic equilibrium of tumor destruction and tumor escape. From this Darwinian-type selection, tumor variants arise that have reduced immunogenicity and grow into clinically apparent tumors. To reestablish immunogenicity, immune cells must regain the ability to sense tumor escape variants. Immune cells can be stimulated by microbially-derived ligands via pathogen recognition receptors, like toll-like receptors (TLRs). TLRs can respond to diverse ligands such as bacterial lipid coat components to viral or bacterial genetic material. My immediate research goal is to understand how TLRs recognize their diverse class of ligands and use this knowledge to develop therapeutic molecules that stimulate, or even inhibit, the immune system. My initial target is toll-like receptor 3 (TLR3), which recognizes double stranded RNA (dsRNA). My hypothesis is that by unraveling the molecular interactions between TLR3 and its dsRNA ligand, the necessary components of a potent immune modulator, such as a vaccine adjuvant, will be defined. The studies use a combination of biochemical, biophysical and biological approaches to define ligand interactions with the receptor and their subsequent effect on immune and cancer cells. Specifically, mutational analysis, cell-based assays and structural analysis of the TLR3:dsRNA complex will further refine our model of ligand recognition. In addition, TLR3 binding to a ligand library will be characterized via gel filtration, ELISA, analytical ultracentrifugation and surface plasmon resonance. Biochemical parameters of ligand binding will be correlated to immune cell stimulation and cancer cell survival. In vivo adjuvant potential of TLR3 ligands will be assessed in a mouse model by antigen-specific T cell production and tumor reduction. The pairing of structure, biochemical and biological experiments will reveal how TLR3 ligands can be used as a switch to wield the power of the immune system. This work will improve public health by developing a vaccine adjuvant that will increase the efficacy of human cancer vaccines and provide a direct, novel therapy for human cancers expressing TLR3.