DCs Regulate Chemokine Responsiveness of Melanoma-Specific T Cells

1型极化DC(ADC 1)显示选择性增强的诱导功能性Th1和CTL的能力(Tef) 细胞，当与目前临床使用的DC(SDC)的“标准”相比。我们目前正在实施 评估Dc1和SDCs诱导黑色素瘤特异性的相对能力的L/11期临床试验 III/IV期黑色素瘤患者的免疫力(UPCI03-118；由独立的R21赠款资助 卡林斯基/柯克伍德)。我们新的初步数据表明，otDc1和sdcs诱导不同的T集合 细胞相关趋化因子受体(CKRs)，其中ADC 1在诱导CXCR3和CCRs方面具有优势 CKRs与黑色素瘤特异性T细胞进入肿瘤有关。我们建议对这一机制进行分析。 ADC和SDCs在肿瘤特异性T细胞中诱导不同CRK表达的差异能力 第四，DC相关信号对DC基癌疫苗的疗效至关重要。我们将检验这一假设 2型反应(传递信号3)也可以差异地调节CKRs在肿瘤中的表达 DC在不同的环境中成熟，除了它们诱导类型1与 特定免疫细胞(传递信号4)。我们将追求三个具体目标： 特异性目的1.确定DC依赖调节T细胞趋化因子的机制 体外反应性。我们将检验这一假设，与当前的范式相反，归纳 不同的CKR谱的调节机制与Th1/Th2承诺不同。 具体目标2.证明DC在不同条件下成熟(ccDc1v.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。我们会直接 验证ocDC1和SDCs可以(以不同方式)调节黑色素瘤特异性CKR模式的假设 T细胞，并能逆转黑色素瘤患者肿瘤诱导T细胞上已建立的CKR模式。 具体目标3.展示当地趋化因子产生的差异和当地的特点 T细胞在DTH部位、原发和转移性肿瘤病变之间渗透。我们将检验这一假设 肿瘤组织构成了一个有偏见的趋化因子环境，并假设原发和 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。 控制肿瘤转移，即使是DTH阳性患者也是如此。 这些研究将有助于我们更好地理解DC依赖的机制和范式 调节癌症免疫，并展望进一步改进黑色素瘤的免疫疗法 和其他肿瘤，通过帮助将疫苗诱导的肿瘤特异性T细胞引导到肿瘤。

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.