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Implication of Macrophages in Tumor Rejection Induced by CpG-oligodeoxynucleotides Without Antigen¹

Fédération de neurologie Mazarin and Institut National de la Santé et de la Recherche Médicale U-495, Hôpital de la Salpêtrière, 75013 [G. A., A. F. C., C. L. C., J-Y. D.], and UPRES 264, Université Paris VI, Hôpital Broussais, 75014 [L. C.], Paris, France

Phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs) display broad immunostimulating activity and have potential applications in cancer immunotherapy. To investigate the antitumor activity of CpG-ODNs and to study the role of macrophages and lymphocytes in tumor rejection, CpG-ODN’s effects on 9 L glioma cells were assessed in Fisher rats, depleted or not in macrophages, in nude mice, and in SCID mice. In nondepleted rats, intratumoral injections with 100 µg of CpG-ODNs on days 5, 12, and 19, after s.c. 9 L cell inoculations, resulted in an 84% reduction of the tumor volumes, when compared with controls injected with saline (P < 0.0001). Whereas all control animals developed tumors, more than one-third of the treated rats remained tumor free. Rejection of established glioma induced a specific long-term immunity, as cured rats were protected against a subsequent 9 L injection, but not a RG2 cell inoculation, another syngenic glioma in Fischer rats. Macrophages played a critical role in the early phase of tumor rejection, because the CpG-ODN’s effects were significantly decreased in the rats depleted in macrophages, and none of the macrophage-depleted rats treated with CpG-ODNs rejected the tumor. On the contrary, both nude and SCID mice, which have normal innate immunity, showed a significant decrease of tumor volume when treated with CpG-ODNs when compared with controls. T cells were however involved in a later phase of the tumor rejection, as all nude mice eventually developed tumors despite the initial tumor growth inhibition.

Altogether, these data suggest that immunostimulatory CpG-ODNs induced tumor rejections through an early activation of innate immunity and priming of a specific immune response against glioma cells.

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