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Expression of Inflammatory Chemokines Combined with Local Tumor Destruction Enhances Tumor Regression and Long-term Immunity¹

Molecular Medicine Program [M. C., M. G., K. H., K. O., J. T., R. G. V.] and Department of Immunology [M. C., R. G. V.], Mayo Clinic, Rochester, Minnesota 55905

Expression of chemokines within tumors can be used to recruit immature dendritic cells (DCs) for the initiation of antitumor T-cell responses. Here, we describe the chemokine receptor expression on murine bone marrow-derived immature DCs. On the basis of these receptor studies, we chose to express the chemokines CCL3 (Mip-1) or CCL20 (Mip-3) in tumors. We show that expression of these chemokines in the colorectal tumor model CMT93 significantly decreases tumorigenesis. This decrease is associated with an increase in CD8 T cells, natural killer cells, and Class II DCs in the tumor within the first 24 h. Furthermore, studies in immunodeficient mice show that both natural killer cells and T cells are required for this decrease in immunogenicity. CCL3 and CCL20 expression alone did not significantly inhibit the development of the B16 melanoma tumor. However, coexpression of the Herpes Simplex Virus thymidine kinase gene (HSVtk) and CCL20, cured large established tumors where HSVtk expression alone was not sufficient. Finally, coexpression of HSVtk with either CCL3 or CCL20 was able to significantly increase protection against subsequent tumor rechallenge.

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