NK- and CD8(+) T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides

Unmethylated cytosine-phosphorothioate-guanine (CpG) containing oligodeoxyn ucleotides (CpG-ODN) are known to act as adjuvants and powerful activators of the innate immune system. We investigated the therapeutic effect of CpG- ODN on a variety of established mouse tumors including AG 104A, IE7 fibrosa rcoma, B16 melanoma, and 3LL lung carcinoma. These tumors are only weakly i mmunogenic and notoriously difficult to treat. Repeated peritumoral injecti on of CpG-ODN resulted in complete rejection or strong inhibition of tumor growth, whereas systemic application had only partial effects. The CpG-ODN- induced tumor rejection was found to be mediated by both INK and tumor-spec ific CD8(+) T cells. Comparison of parental tumors and variants rendered mo re antigenic by transfection with tumor Ags suggested that the efficiency o f the CpG-ODN therapy correlated with the antigenicity of the tumors. Perit umoral CpG-ODN treatment was even effective in a situation where the immune system was tolerant for the tumor Ag, as shown by breakage of tolerance an d tumor elimination. These results suggest that peritumoral application of CpG-ODN acts locally by inducing NK cells, and also leads to efficient pres entation of tumor Ags and stimulation of CD8(+) effector and memory T cells , thus providing a powerful antitumor therapy that can be also applied with out knowledge of the tumor Ag.