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 implementinga phase l/ll clinical trial evaluating the relative abilities of DDC1 and sDCs to induce melanoma-specificimmunity in stage III/IV melanoma patients (UPCI 03-118; funded by an independent R21 grant toKalinski/Kirkwood). Our new preliminary data demonstrate that otDC1 and sDCs induce different sets of Tcell-associated chemokine receptors (CKRs), with aDC1s being superior in inducing CXCR3 andCCRS, theCKRs implicated in tumor-entry of melanoma-specific T cells. We propose to analyze the mechanism of thedifferential ability of aDC1 and sDCs to induce distinct CRK expression in tumor-specific T cells, as thefourth DC-related signal essential for the efficacy of DC-based cancer vaccines. We will test the hypothesistype 2 responses (delivery of signal 3), can also differentially regulate the expression of CKRs in tumorthatDCs maturing in different environments, in addition to their differential ability to induce type-1 versusspecific 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 chemokineresponsiveness in vitro. We will test the hypothesis that, in contrast to the current paradigm, the inductionof 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) differentiallyregulate chemokine responsiveness of melanoma-specific T cells in vitro and in vivo. We will directlytest the hypothesis that ocDC1 and sDCs can (differentially) modulate the CKR patterns in melanoma-specificT 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 localT cell infiltrates between DTH sites, primary, and metastatic tumor lesions. We will test the hypothesisthat the tumor tissues constitute a biased chemokine environment and the hypothesis that primary andmetastatic tumors represent different chemokine environments, contributing to often ineffective immunecontrol of tumor metastases, even in DTH-positive patients.The proposed studies will help us to better understand the mechanisms and paradigms of DC-dependentregulation of cancer immunity, and to prospectively develop further improved immunotherapies of melanomaand other tumors, by helping to direct the vaccination-induced tumor-specific T cells to the tumors.
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