Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen.
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 microg 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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Fédération de neurologie Mazarin and Institut National de la Santé et de la Recherche Médicale U-495, Hôpital de la Salpêtrière, 47 boulevard de l'hôpital, 75013 Paris, France.
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Chen
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Le Clanche
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Delattre
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D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007114:Immunization; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides