| Despite immunogenicity, melanoma-specific vaccines have demonstrated minimal clinical efficacy in patients with established disease, but enhance survival when administered in the adjuvant setting. It has been shown that T cell infiltration of melanoma is associated with enhanced clinical efficacy and is a desirable endpoint of immunotherapeutic vaccination. T cell infiltration into tumors is regulated, in part, by chemokine receptors. Therefore, we have investigated the chemokine receptor CXCR3 in three different settings. 1) The induction of CXCR3 on CD8 T cells by peptide vaccination in human patients, 2) the requirement for CXCR3 expression on CD8 T cells for the infiltration of metastatic melanoma lesions in the lungs of mice, and 3) the requirement for host CXCR3 expression for engraftment of metastatic melanoma in the lung.;Our results are three-fold. 1) We determined that vaccination of a melanoma peptide vaccine in adjuvant induces tumor antigen-specific CD8 T cells that are predominantly positive for CXCR3. These cells express high levels of Tbet, IFN-gamma, and IL-12R-beta1, and thus maintain a phenotype that supports the infiltration and eradication of melanoma. 2) We demonstrated that CXCR3 is required for efficient infiltration of tumor-bearing lungs. Additionally, we observed temporal regulation of CXCR3-cognate chemokines with the establishment of melanoma metastases in the lung. This correlated with temporal regulation of T cell infiltration.;We demonstrated that blocking adenosine signaling in the tumor microenvironment restored chemokine production and T cell infiltration in advanced metastatic lesions. 3) Host expression of CXCR3 is required for the engraftment of pulmonary melanoma metastases. We observed that CXCR3-/- mice were protected from melanoma engraftment in the lung, as early as 24 hours after tumor cell injection. We determined that a CXCR3+ host cell was mediating this differential engraftment, and determined that eliminating macrophages in C57BL/6 mice could reduce melanoma engraftment of the lung to levels seen in CXCR3-/- mice.;We show that CXCR3 and its ligands play a crucial role in both immune-mediated regulation, and metastatic dissemination, of melanoma. Therefore, regulation of CXCR3 expression on lymphocytes and CXCR3 ligands in the tumor microenvironment will be critical for optimizing immune-mediated therapy of melanomas (and likely other tumors). |
