Targeted Disruption of Tumor-Derived Chemokine Synthesis and Reversal of Tumor-Induced Immune Suppression

摘要

Chemokines play a pivotal role in the maturation of the immune system, and in the initiation, and maintenance of an immune response. Because of their key role in the immune response, the aberrant expression of chemokines can have a profound effect on the ability of T cells to respond to antigen. We have found that several breast cancer cell lines produced chemokines capable of recruiting T cells. However, instead of increasing anti-tumor immunity, the tumor-derived chemokines may have prevented an effective immune response by desensitizing T-cell chemokine receptors. Our hypothesis is that disrupting the synthesis of tumor-derived chemokines (using anti-sense technology) will remove tumor- induced immune suppression and enhance the immunogenicity of the tumor. In order to test this hypothesis we generated stable clones that lack CCL2 and CCL5 production compared to the parental tumor cell line. Using these tumors we found that both CCL2 and CCL5 impair the T cell response to the murine mammary carcinoma 4Tl. Moreover, tumor-derived CCL5 impaired T cell chemotactic activity and enhanced growth of the tumor in vivo. In addition, we found that tumor- derived CXCL 1 acts as an autocrine growth factor and angiogenesis factor for 4T 1.