Modulating CXCR3 chemokine expression in the tumor microenvironment as a therapeutic approach for skin cancers. (P2074)

Abstract

Abstract Chemokines can inhibit or promote tumor growth through multiple mechanisms such as inhibition or promotion of angiogenesis or recruiting effector or regulatory cells into tumor. Modulation of intra-tumor chemokine expression is considered to be a promising approach of cancer immunotherapy. CXCR3 chemokines (CXCL9/Mig and CXCL10/IP-10) are known as potent tumor suppressors that inhibit tumor angiogenesis and recruit Th1 and NK cells into the tumor. We used murine model of aggressive skin cancer (cutaneous sarcoma or melanoma) to test the induction of Mig expression within tumors as a therapeutic approach. Intra-tumor delivery of Mig DNA by retroviral vector or by plasmid suppressed growth of MCA205 sarcoma and B16 melanoma. This therapeutic effect was T cell-dependent and was mediated through enhancing the activation of tumor-specific T cells by tumor-infiltrating dendritic cells rather than through angiostatic functions of Mig. Surprisingly, the deficiency of tumor hosts in IP-10 resulted in the suppression of tumor growth and increased activation of tumor-specific T cells similar to the therapeutic effects mediated by overexpression of Mig. These results suggest that besides similar angiostatic and chemoattracting functions, Mig and IP-10 impose non-redundant and even antagonistic effects on anti-tumor immunity and that the induction of Mig expression and simultaneous inhibition of IP-10 in tumor hosts might be a potent therapeutic approach to treat aggressive skin cancers.