DCs Regulate Chemokine Responsiveness of Melanoma-Specific T Cells

1型极化DC（aDC 1 s）表现出选择性增强的诱导功能性Th 1和CTL（Teff）的能力 细胞，当与临床使用的DC（sDC）的当前“标准”相比时。我们目前正在实施 评价DDC 1和sDC诱导黑素瘤特异性免疫应答的相对能力的I/II期临床试验 III/IV期黑色素瘤患者的免疫力（UPCI 03-118;由独立的R21赠款资助， Kalinski/柯克伍德）。我们的新的初步数据表明，otDC 1和sDC诱导不同的T细胞集。 细胞相关趋化因子受体（CKR），aDC 1在诱导CXCR 3和CCRS方面具有上级优势， CKR参与黑色素瘤特异性T细胞的肿瘤进入。我们建议分析的机制， aDC 1和sDC在肿瘤特异性T细胞中诱导不同CRK表达的差异能力， 第四个DC相关信号对基于DC的癌症疫苗的功效至关重要。我们将检验这个假设 2型反应（信号3的传递）也可以差异调节肿瘤中CKR的表达， 在不同环境中成熟的DC，除了它们诱导1型与2型分化的能力不同之外， 特异性免疫细胞（信号4的传递）。我们将追求三个具体目标： 具体目标1。确定DC依赖性调节T细胞趋化因子的机制 体外反应性。我们将检验这样一个假设，即与当前的范式相比， 不同CKR概况的调节机制与Th 1/Th 2承诺不同。 具体目标2。证明在不同条件下成熟的DC（ccDC 1与sDC） 在体外和体内调节黑色素瘤特异性T细胞的趋化因子反应性。我们会直接 检验ocDC 1和sDC可以（差异地）调节黑色素瘤特异性细胞中的CKR模式的假设 T细胞，并且可以逆转黑色素瘤患者中肿瘤诱导的T细胞上建立的CKR模式。 具体目标3。展示局部趋化因子产生的差异和局部趋化因子的特征。 DTH部位、原发性和转移性肿瘤病变之间的T细胞浸润。我们将检验这个假设 肿瘤组织构成了一个偏向趋化因子的环境， 转移性肿瘤代表不同的趋化因子环境，导致通常无效的免疫应答。 控制肿瘤转移，即使在DTH阳性患者中。 这些研究将有助于我们更好地理解DC依赖性的机制和范式 调节癌症免疫，并前瞻性地开发进一步改进的黑色素瘤免疫疗法 和其他肿瘤，通过帮助引导疫苗诱导的肿瘤特异性T细胞到肿瘤。

Type-1 polarized DCs (aDC1s) show selectively enhanced ability to induce functional Th1 and CTL (Teff) cells, when compared to the current "standard" of clinically-used DCs (sDC). We are currently implementing a phase l/ll clinical trial evaluating the relative abilities of DDC1 and sDCs to induce melanoma-specific immunity in stage III/IV melanoma patients (UPCI 03-118; funded by an independent R21 grant to Kalinski/Kirkwood). Our new preliminary data demonstrate that otDC1 and sDCs induce different sets of T cell-associated chemokine receptors (CKRs), with aDC1s being superior in inducing CXCR3 andCCRS, the CKRs implicated in tumor-entry of melanoma-specific T cells. We propose to analyze the mechanism of the differential ability of aDC1 and sDCs to induce distinct CRK expression in tumor-specific T cells, as the fourth DC-related signal essential for the efficacy of DC-based cancer vaccines. We will test the hypothesis type 2 responses (delivery of signal 3), can also differentially regulate the expression of CKRs in tumorthat DCs maturing in different environments, in addition to their differential ability to induce type-1 versus specific immune cells (delivery of signal 4). We will pursue three Specific Aims: Specific Aim 1. Determine the mechanism of DC-dependent regulation of T cell chemokine responsiveness in vitro. We will test the hypothesis that, in contrast to the current paradigm, the induction of a distinct CKR profile is regulated in a different mechanism than the Th1/Th2 commitment. Specific Aim 2. Demonstrate that DCs maturing in different conditions (ccDC1 v. sDC) differentially regulate chemokine responsiveness of melanoma-specific T cells in vitro and in vivo. We will directly test the hypothesis that ocDC1 and sDCs can (differentially) modulate the CKR patterns in melanoma-specific T cells, and can revert the established CKR patterns on the tumor-induced T cells in melanoma patients. Specific Aim 3. Demonstrate the differences in local chemokine production and the character of local T cell infiltrates between DTH sites, primary, and metastatic tumor lesions. We will test the hypothesis that the tumor tissues constitute a biased chemokine environment and the hypothesis that primary and metastatic tumors represent different chemokine environments, contributing to often ineffective immune control of tumor metastases, even in DTH-positive patients. The proposed studies will help us to better understand the mechanisms and paradigms of DC-dependent regulation of cancer immunity, and to prospectively develop further improved immunotherapies of melanoma and other tumors, by helping to direct the vaccination-induced tumor-specific T cells to the tumors.