We will test the hypothesis that the ability of DCs and other tumor-associated cells to produce distinct sets of chemokines (CK)and to attract functionally different subsets of immune cells is determined in a tumor- specific manner by distinct inflammatory mediators. Furthermore, we hypothesize that pharmacological modulation of tumor CK environment can be used to selectively promote the tumor entry of the vaccination- induced type-1 effector T cells (Jeff: Th1 and CTL) with defined expression of CK receptors, but not Tregs. Our goal is to develop reliable treatments with tumor-matched combinations of pharmacologic agents to selectively enhance the production of the Teff-attracting CKs within tumor lesions, in order to promote the clinical efficacy of cancer immunotherapies. Based on our Preliminary data, we expect that we will be able to identify the combination treatments with double selectivity: A) selectively enhancing the production of Jeff- attracting CKs without enhancing Treg-attracting CKs;and B) preferentially effective in tumor lesions, rather than healthy tissues. Contrasting melanoma and colorectal cancer, the tumors metastasizing to the same organ (liver), we will determine the respective roles of the histological type of tumor versus the site of its implantation in determining local CK production, will identify the cellular and molecular mechanisms of different CK production between healthy tissues, primary and metastatic cancer, and the mechanisms of the differential responsiveness of such tissues to particular CK-modulating agents. Within Specific Aim 1, we will determine which tumor-specific inflammatory factors, selectively relevant to melanoma or to CRC,determine the CK production by tumor-associated cells in vitro and dictate the recruitment of functionally-different subsets of immune cells. We will analyze the impact of such factors on the ability of isolated DCs and other tumor-associated cell types to produce the Jeff-attracting- versus Treg- attracting CKs, and to preferentially attract Te/f v. Treg cells. Within Specific Aim2, we will determine the mechanisms of differences in CK regulation between CRC, melanoma, and healthy tissues, and will develop the methods to correct the balance between the Te/fv Treg-attracting CKs in melanoma and CRC tumors, using human ex vivo models of tumor explant cultures and mouse in vivo models of primary and metastatic tumors. Within Specific Aim 3, we will perform preclinical mouse studies testing the synergism of cancer vaccines and chemokine-regulatory regimens against primary and metastatic cancers, followed by phase clinical trials of selected therapies with DC-based vaccines combined with the prioritized tumor-selective CK- modulating regimens in patients with liver-metastatic CRC and patients with melanoma in transit.
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