Given the recalcitrant nature of melanoma to conventional therapies, there exists a critical need for successful clinical immunotherapy to treat metastatic melanoma. The objective of most clinical immunotherapy trials has been to generate maximal numbers of circulating tumor- specific cytotoxic T lymphocytes (CTL), predicated on the notion that "more is better." However, the correlation between magnitude of vaccine-induced CD8+ T cells and the objective clinical responses remains weak, suggesting that the inefficacy of immune therapy results from the qualitative failure of vaccine-induced T cells to efficiently activate, infiltrate tumor, and develop robust memory populations. Therefore, we have examined several qualitative aspects of tumor Ag-specific T cells from melanoma patients that have been vaccinated with multiple melanocyte differentiation protein-derived antigens in an adjuvant setting. We demonstrated a significant association between the expression of CXCR3 by circulating tumor-specific CD8+ T cells and the maintenance of disease-free status or survival, suggesting either that CXCR3 expression a) is functionally required for the T cell-mediated immunologic control of metastatic tumors, or b) serves as a marker of qualitatively-superior anti-tumor T cells. In the present proposal, we delineate three aims that will expand upon our initial findings and evaluate the mechanisms by which CXCR3 and its biological axis of molecules act to enhance immune-mediated tumor control. Specifically, we will relate CXCR3 expression in the human CD8 compartment to 1) immunization-induced polarization phenotype;2) anti-tumor functionality;3) and access to metastatic tumor compartments. We will use human tissues and samples for correlative studies and mouse models for mechanistic studies. Key deliverables of this research will include basic science knowledge with translational potential, including: 1) enhanced understanding of the regulation of CXCR3 expression and T cell polarization in human CD8+ T cells;2) evaluation of the prognostic utility of CXCR3 expression as a marker of vaccine response and means to prospectively evaluate patient-specific response potential;and 3) new immunologic targets for intervention, so as to optimize the therapeutic potential of immunogenic vaccines.
We will evaluate the phenotype of vaccine-activated CD8+ cells in patients with metastatic melanoma, and then correlate qualitative functional aspects of these cells with clinical outcomes to determine the optimal type of T cell for rejection and control of cancer. We will also evaluate the phenotype of CD8+ T cells that infiltrate metastatic melanomas in human and use mouse models to evaluate the molecular and cellular mechanisms that govern T cell migration. Collectively, these studies will make new observations about the fundamental biology of T cell activation and migration in humans and establish the basis to optimize cancer vaccines by enhancing T cell infiltration of metastatic melanomas.
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