Role of CXCR3 for CD8+ T cells in cancer immunotherapy

描述(申请人提供)：鉴于黑色素瘤对传统疗法的顽固性，迫切需要成功的临床免疫疗法来治疗转移性黑色素瘤。大多数临床免疫治疗试验的目标一直是产生最大数量的循环中的肿瘤特异性细胞毒性T淋巴细胞(CTL)，这是基于“越多越好”的概念。然而，疫苗诱导的CD8+T细胞的数量与客观的临床反应之间的相关性仍然很弱，这表明免疫治疗的无效是由于疫苗诱导的T细胞在质量上未能有效地激活、渗透到肿瘤并形成强大的记忆群体。因此，我们对在佐剂环境下接种了多种黑素细胞分化蛋白衍生抗原的黑色素瘤患者的肿瘤抗原特异性T细胞的几个定性方面进行了检测。我们证明了循环中肿瘤特异性CD8+T细胞表达CXCR3与维持无病状态或生存之间的显著关联，这表明CXCR3的表达a)是T细胞介导的对转移肿瘤的免疫控制所必需的，或者b)是质量上优越的抗肿瘤T细胞的标志。在目前的提案中，我们描述了三个目标，这些目标将在我们初步发现的基础上进行扩展，并评估CXCR3及其分子的生物轴增强免疫介导的肿瘤控制的机制。具体地说，我们将把CXCR3在人类CD8隔间的表达与1)免疫诱导极化表型；2)抗肿瘤功能；3)和对转移肿瘤隔间的接触联系起来。我们将使用人体组织和样本进行相关研究，并使用小鼠模型进行机制研究。这项研究的主要成果将包括具有翻译潜力的基础科学知识，包括：1)加强对人类CD8+T细胞中CXCR3表达和T细胞极化调节的了解；2)评估CXCR3表达作为疫苗应答标志的预后效用，以及前瞻性评估患者特异性应答潜力的手段；以及3)新的免疫学干预靶点，以优化免疫原性疫苗的治疗潜力。公共卫生相关性：我们将评估转移性黑色素瘤患者中疫苗激活的CD8+细胞的表型，然后将这些细胞的质量功能方面与临床结果相关联，以确定用于排斥和癌症控制的最佳T细胞类型。我们还将评估渗入人类转移性黑色素瘤的CD8+T细胞的表型，并使用小鼠模型评估控制T细胞迁移的分子和细胞机制。总之，这些研究将对人类T细胞激活和迁移的基本生物学进行新的观察，并为通过增强转移性黑色素瘤的T细胞渗透来优化癌症疫苗奠定基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.