Abstract
CpG oligodeoxynucleotides (CpG ODNs), the artificial versions of unmethylated CpG motifs that were originally discovered in bacterial DNA, are demonstrated not only as potent immunoadjuvants but also as anticancer agents by triggering toll-like receptor 9 (TLR9) activation in immune cells. TLR9 activation triggered by CpG ODN has been shown to activate plasmacytoid dendritic cells (pDCs) and cytotoxic T lymphocytes (CTLs), enhancing T cell-mediated antitumor immunity. However, the extent of antitumor immunity carried by TLR agonists has not been optimized individually or in combinations with cancer vaccines, resulting in a decreased preference for TLR agonists as adjuvants in clinical trials. Although various combination therapies involving CpG ODNs have been applied in clinical trials, none of the CpG ODN-based drugs have been approved by the FDA, owing to the short half-life of CpG ODNs in serum that leads to low activation of natural killer cells (NK cells) and CTLs, along with increases of pro-inflammatory cytokine productions. This review summarized the current innovation on CpG ODNs that are under clinical investigation and explored the future direction for CpG ODN-based nanomedicine as an anticancer monotherapy.
Highlights
ODNs have been applied in clinical trials, none of the CpG ODN-based drugs have been approved by the FDA, owing to the short half-life of CpG ODNs in serum that leads to low activation of natural killer cells (NK cells) and cytotoxic T lymphocytes (CTLs), along with increases of pro-inflammatory cytokine productions
Toll-like receptor 9 (TLR9), a pattern recognition receptor expressed on endosomal surfaces of immune cells, recognizes unmethylated CpG di-deoxynucleotide motifs in bacterial or viral DNAs and synthetic CpG oligodeoxynucleotides (CpG ODNs)
The binding of CpG ODNs to TLR9 induces a conformational change of TLR9, which is thought to result in differential recruitment of one or more TIR domain-containing adaptors
Summary
It is known that bacterial DNA is a potent stimulus to immune systems, while the most active sequence in bacterial DNAs is the unmethylated CpG di-deoxynucleotide motif. ODNs have been demonstrated to activate plasmacytoid dendritic cells (pDCs) to secrete type I IFNs and express a high level of co-stimulatory molecules for T cell binding and maturation, such as CD80 and CD86 [5]. Th2 cells-mediated antitumor immunity involves the recruitment of eosinophils to the tumor microenvironment (TME) through IL-4 and IL-13 feedback loops, the anti-inflammatory cytokines produced by Th2 cell polarization may have controversial effects on regulatory T cell (Treg) induction, which may hamper the Th1 antitumor immunity [13,14]. IL-17 secreted by Th17 cells could activate CTLs and convert them into IFNγ-producing effector T cells, in concordance with Th1-mediated antitumor immunity [17,18]. MDSC-secreted IL-10 and TGFβ are implicated in effector T cell suppression and Treg induction [28,29,30]
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