Role of CXCR3 for CD8+ T cells in cancer immunotherapy

鉴于黑色素瘤对常规疗法的排斥性， 用于治疗转移性黑色素瘤的成功临床免疫疗法。大多数人的目标 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”的概念。“然而， 疫苗诱导的CD 8 + T细胞数量与客观临床 反应仍然很弱，这表明免疫治疗的无效性是由于 疫苗诱导的T细胞不能有效地活化、浸润肿瘤和发展 强大的记忆群体。因此，我们检查了肿瘤的几个定性方面， 已接种多种黑素细胞的黑色素瘤患者的Ag特异性T细胞 分化蛋白衍生的抗原在佐剂环境中。我们展示了一个重要的 循环肿瘤特异性CD 8 + T细胞表达CXCR 3与 维持无病状态或存活，表明CXCR 3表达a） 是转移性肿瘤的T细胞介导的免疫控制功能上所需的，或B） 作为优质抗肿瘤T细胞的标志物。在本提案中，我们 描述三个目标，将扩大我们的初步研究结果和评估机制， 其中CXCR 3及其生物学轴分子的作用是增强免疫介导的肿瘤 控制具体而言，我们将人CD 8区室中的CXCR 3表达与1） 免疫诱导极化表型; 2）抗肿瘤功能; 3）和获得 转移性肿瘤隔室。我们将使用人体组织和样本进行相关研究 和用于机理研究的小鼠模型。这项研究的主要成果将包括基本的 具有转化潜力的科学知识，包括：1）加强对 人CD 8 + T细胞中CXCR 3表达和T细胞极化的调节; 2）评估 CXCR 3表达作为疫苗应答标志物的预后效用以及 前瞻性评估患者特异性反应潜力;和3）新的免疫靶点， 干预，以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.