CC-chemokine ligand 17 gene therapy induces tumor regression through augmentation of tumor-infiltrating immune cells in a murine model of preexisting CT26 colon carcinoma

Chemokines, which regulate leukocyte trafficking and infiltration of local sites, are attractive candidates for improving the efficacy of cancer immunotherapy by enhancing the accumulation of immune cells in tumor tissue. Herein, we evaluated the antitumor effects of intratumoral injection of RGD fiber-mutant adenoviral vectors (AdRGDs) encoding the chemokines CCL17, CCL19, CCL20, CCL21, CCL22, CCL27, XCL1 or CX3CL1 in a murine model of preexisting CT26 colon carcinoma. Among these 8 chemokine-expressing AdRGDs, injection of AdRGD-CCL17 most effectively induced tumor regression and generated specific immunity in rechallenge experiments. Tumor elimination activity by intratumoral injection of AdRGD-CCL17 depended on both the vector dose and the number of injections, and mainly required CD8+ CTLs in an effector phase as confirmed by analysis using BALB/c nude mice and an in vivo depletion assay. In addition, CCL17 gene transduction induced significant increases in the number of infiltrating macrophages and CD8+ T cells in CT26 tumors, and changed the tumor microenvironment to an immunologic activation state in which there was enhanced expression of lymphocyte activation markers and cell adhesion molecules. Thus, our data provide evidence that CCL17 gene transduction of local tumor sites is a promising approach for the development of a cancer immunogene therapy that can recruit activated tumor-infiltrating immune effector cells.