Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs

被引:217
作者
Ballas, ZK
Krieg, AM
Warren, T
Rasmussen, W
Davis, HL
Waldschmidt, M
Weiner, GJ
机构
[1] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA
[2] Dept Vet Affairs Med Ctr, Iowa City, IA 52246 USA
[3] Univ Iowa, Coll Med, Holden Canc Ctr, Iowa City, IA 52242 USA
[4] Coley Pharmaceut Grp, Wellesley, MA 02481 USA
[5] Ottawa Hosp, Loeb Hlth Res Inst, Ottawa, ON, Canada
[6] Univ Ottawa, Loeb Hlth Res Inst, Ottawa, ON, Canada
关键词
D O I
10.4049/jimmunol.167.9.4878
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Immune stimulatory oligodeoxynucleotides (ODN) with unmethylated CpG motifs are potent inducers of both innate and adaptive immunity. It initially appeared that a single type of optimal CpG motif would work in all applications. We now report that specific motifs of CpG ODN can vary dramatically in their ability to induce individual immune effects and that these differences impact on their antitumor activity in different tumor models. In particular, a distinct type of CpG motif, which has a chimeric backbone in combination with poly(G) tails, is a potent inducer of NK lytic activity but has little effect on cytokine secretion or B cell proliferation. One such NK-optimized CpG ODN (1585) can induce regression of established melanomas in mice. Surprisingly, no such therapeutic effects were seen with CpG ODN optimized for activation of B cells and Th1-like cytokine expression (ODN 1826). The therapeutic effects of CpG 1585 in melanoma required the presence of NK but not T or B cells and were not associated with the induction of a tumor-specific memory response. In contrast, CpG 1826, but not CpG 1585, was effective at inducing regression of the EL4 murine lymphoma; this rejection was associated with the induction of a memory response and although NK cells were necessary, they were not sufficient. These results demonstrate that selection of optimal CpG ODN for cancer immunotherapy depends upon a careful analysis of the cellular specificities of various CpG motifs and an understanding of the cellular mechanisms responsible for the antitumor activity in a particular tumor.
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页码:4878 / 4886
页数:9
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