CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1

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.