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.
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Peng
P
Yin
Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Xin
X
Liu
Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Aaron S
AS
Mansfield
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Susan M
SM
Harrington
Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Yinghua
Y
Li
Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Yiyi
Y
Yan
Department of Urology, Mayo Clinic, Rochester, MN, USA.|Department of Immunology, Mayo Clinic, Rochester, MN, USA.
Haidong
H
Dong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018664:Interleukin-12
CpG ODN; IL-12; PD-1; immune checkpoints; tumor immunotherapy