Integrating individual functional moieties of CXCL10 and CXCL11 into a novel chimeric chemokine leads to synergistic antitumor effects: a strategy for chemokine-based multi-target-directed cancer therapy

摘要

The complexity of tumor biology necessitates a multimodality approach that targets different aspects of tumor environment in order to generate the greatest benefit. IFN-inducible T cell α chemoattractant (ITAC)/CXCL11 and IFN-inducible protein 10 (IP10)/CXCL10 could exert antitumor effects with functional specificity and thus emerge as attractive candidates for combinatorial strategy. Disappointedly, a synergistic antitumor effect could not be observed when CXCL10 and CXCL11 were pooled together. In this regard, we seek to improve antitumor efficacy by integrating their individual functional moieties into a chemokine chimeric molecule, designated ITIP, which was engineered by substituting the N-terminal and N-loop region of CXCL10 with those of CXCL11. The functional properties of ITIP were determined by chemotaxis and angiogenesis assays. The antitumor efficacy was tested in murine CT26 colon carcinoma, 4T1 mammary carcinoma and 3LL lung carcinoma. Here we showed that ITIP not only exhibited respective functional superiority but strikingly promoted regression of established tumors and remarkably prolonged survival of mice compared with its parent chemokines, either alone or in combination. The chemokine chimera induced an augmented anti-tumor immunity and a marked decrease in tumor vasculature. Antibody neutralization studies indicated that CXCL10 and CXCL11 moieties of ITIP were responsible for anti-angiogenesis and chemotaxis in antitumor response, respectively. These results indicated that integrating individual functional moieties of CXCL10 and CXCL11 into a chimeric chemokine could lead to a synergistic antitumor effect. Thus, this integration strategy holds promise for chemokine-based multiple targeted therapy of cancer.