Role of CXCR3 for CD8+ T cells in cancer immunotherapy

考虑到黑色素瘤对传统疗法的顽固性，存在着迫切的需要 成功的临床免疫疗法治疗转移性黑色素瘤。社会变革管理计划的目标 临床免疫治疗试验已经产生了最大数量的循环肿瘤- 特异性细胞毒性T淋巴细胞(CTL)，基于“越多越好”的理念。然而， 疫苗诱导的CD8 T细胞数量与客观临床的相关性 反应仍然很弱，这表明免疫治疗的无效是由于 疫苗诱导的T细胞有效激活、渗入肿瘤和发展的质的失败 强大的内存群体。因此，我们检查了肿瘤的几个定性方面。 黑色素瘤患者接种多个黑素细胞后的Ag特异性T细胞 佐剂环境中的分化蛋白衍生抗原。我们展示了一个意义重大的 循环肿瘤特异性CD8 T细胞表达CXCR3与 保持无病状态或存活，表明CXCR3表达a) 是T细胞介导的转移性肿瘤免疫控制所必需的功能，或b) 作为定性优越的抗肿瘤T细胞的标志物。在目前的提案中，我们 勾勒出三个目标，这些目标将扩展我们的初步发现，并通过以下方式评估机制 CXCR3及其生物轴在增强免疫介导的肿瘤中的作用 控制力。具体地说，我们将人CD8隔室中CXCR3的表达与1) 免疫诱导极化表型；2)抗肿瘤功能；3)和获得 转移性肿瘤隔间。我们将使用人体组织和样本进行相关研究 以及用于机械学研究的小鼠模型。这项研究的主要交付成果将包括基本 具有翻译潜力的科学知识，包括：1)加强对 人CD8 T细胞中CXCR3表达和T细胞极化的调节；2)评价 CXCR3表达作为疫苗应答和治疗手段的预后作用 前瞻性评估患者特异性反应潜力；以及3)新的免疫学靶点 干预，从而优化免疫原性疫苗的治疗潜力。

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.