Divergent Therapeutic and Immunologic Effects of Oligodeoxynucleotides with Distinct CpG Motifs

Abstract

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.

Maximizing CD8+ T cell responses elicited by peptide vaccines containing CpG oligodeoxynucleotides

“…Human recombinant IL-2 was obtained from the National Cancer Institute Biological Resources Branch. The CpG used in our experiments, CpG 1826 [26], was purchased from Coley Pharmaceutical Group. Incomplete Freund's Adjuvant (IFA) was purchased from Sigma.…”

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

“…A/D-type CpG DNAs can induce cytokine production in a variety of cells, but exhibit weaker ability to induce proliferation and IgM production of splenocytes than conventional CpG DNAs (4). Notably, A/D-type CpG DNAs have greater ability to induce IFN-␣ production from plasmacytoid DC (PDC) and IFN-␥ from NK cells (5,6).…”

CpG Oligodeoxynucleotides Downregulate Placental Adiponectin and Increase Embryo Loss in Non‐Obese Diabetic Mice

“…There are three classes of stimulatory CpG ODNs: class A (ODN 2216), class B (ODN 2006), and class C (ODN 2395), each with their own control. ODN 2216 (induce high IFN‐α production), 2006 (strongly active B cells), and 2395 (combine features of both ODN 2216 and ODN 2006) are specific for human tissues 19, 20. Following stimulation with 25 n m forskolin for 24 hr, the medium (25 n m forskolin, 1% FBS) was refreshed, and each of the three classes of CpG ODNs and their respective controls were added to at a concentration of 5 μ m according to the manufacturer's instructions for another 48 hr of culture.…”