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Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen
G Auf1, A F Carpentier, L Chen
1Fédération 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.
Abstract:
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.
Insights
CpG-oligodeoxynucleotides (CpG-ODNs) show significant antitumor activity against 9 L glioma cells in rats by activating innate immunity. Macrophages are crucial for early tumor rejection, while T cells contribute to long-term immunity against glioma.
Area of Science:
- Immunology
- Cancer Research
- Oligonucleotide Therapeutics
Background:
- CpG-oligodeoxynucleotides (CpG-ODNs) are known for their immunostimulating properties.
- CpG-ODNs have potential applications in cancer immunotherapy.
- Understanding the roles of macrophages and lymphocytes in tumor rejection is critical.
Purpose of the Study:
- To investigate the antitumor activity of CpG-ODNs against 9 L glioma cells.
- To elucidate the roles of macrophages and lymphocytes in CpG-ODN-mediated tumor rejection.
Main Methods:
- CpG-ODN effects were assessed in Fisher rats (macrophage-depleted and non-depleted), nude mice, and SCID mice bearing 9 L glioma cells.
- Intratumoral injections of CpG-ODNs were administered at specific time points post-inoculation.
- Tumor volumes were measured and compared between treated and control groups.
Main Results:
- Intratumoral CpG-ODN injections led to an 84% reduction in tumor volumes in non-depleted rats, with some rats remaining tumor-free.
- Macrophage depletion significantly decreased the antitumor effects of CpG-ODNs, indicating a critical role for macrophages in early rejection.
- Nude and SCID mice showed significant tumor volume reduction, but T cell involvement was noted in later stages of rejection.
Conclusions:
- Immunostimulatory CpG-ODNs effectively induce tumor rejection against 9 L glioma.
- Early tumor rejection relies on the activation of innate immunity, particularly macrophages.
- CpG-ODNs prime a specific immune response essential for long-term tumor control and immunity.