The first step in the generation of
tumor immunity is the migration of dendritic cells (DCs) to the apoptotic
tumor, which is presumed to be mediated by various
chemokines. To clarify the roles of
chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following
tumor apoptosis. We injected mice with a murine
hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-
thymidine kinase (tk) gene and then treated the animals with
ganciclovir (GCV). GCV treatment induced massive
tumor cell apoptosis accompanied with intratumoral DC infiltration.
Tumor-infiltrating DCs expressed
chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a
ligand for CCR1 and CCR5. Moreover,
tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary
tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their
ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of
tumor immunity following induction of
tumor apoptosis by suicide genes.