Abstract
CpG oligodeoxynucleotides, as a ligand of toll-like receptor (TLR)-9, have demonstrated promising antitumor effects in some clinical trials; however, its toxicity and low efficacy as a systemic therapy has limited its therapeutic applications. In order to improve its therapeutic efficacy, we investigated the mechanisms of CpG-induced antitumor immunity in the context of CD8+ T cell responses. We show that IL-12 is required for the expansion of IFN-γ producing tumor-reactive CD8+ T cells capable of rejecting tumors. In addition, CpGs reduced PD-1 expression by effector CD8+ T cells via the IL-12 pathway. The combination of CpG and PD-1 blockade show a synergistic effect in generation of systemic antitumor immunity. Our studies define a critical role of IL-12 in CpG-induced antitumor immunity and provide a rationale for combined therapy with TLR agonists and immune checkpoint blockade in cancer treatment.
Highlights
CpG oligodeoxynucleotides (ODN) are DNAs containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotides
To understand the role of IL-12 in antitumor immunity induced by Toll-like receptor (TLR) ligands, we compared the antitumor function of the TLR9 ligand CpG and TLR3 ligand Poly I:C among wild type (WT) mice and IL-12 deficient (KO) mice
Our results suggest that IL-12 is required in CpG-induced antitumor immunity
Summary
CpG oligodeoxynucleotides (ODN) are DNAs containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotides. Since the unmethylated CG sequence is characteristic of bacterial DNA and injection of dead bacteria occasionally shows antitumor effects in humans [1], CpGs have been explored as an immune adjuvant in the treatment of human cancers [2, 3]. Through its recognition by Toll-like receptor (TLR)-9 [5], CpGs induce the production of cytokines from dendritic cells, including IL-12 [6], and initiate a cascade of innate and adaptive immune responses to tumors [7]. It has been reported that intratumoral injection of CpGs stimulates the production of IL-12 and other Th1 cytokines that promote antitumor immunity [8]. The influence of IL-12 on CpG-induced antitumor CD8+ T cell responses is not fully understood
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