Discrepant antitumor efficacies of three CpG oligodeoxynucleotide classes in monotherapy and co-therapy with PD-1 blockade.

Abstract

Unmethylated CpG oligodeoxynucleotides (ODNs) activate plasmacytoid dendritic cells (pDCs) and B cells to induce humoral and cellular immunity, and are under development for the treatment of multiple cancers. However, the specific differences in antitumor effects among the three CpG ODN classes when administered as a monotherapy or in co-therapy with the anti-PD-1 antibody are unclear. We compared the immunostimulatory effects in vitro and antitumor effects in a CT26 subcutaneous mouse tumor model among the three CpG ODN classes. We found that CpG-A slightly suppressed tumor growth but possessed no synergistic antitumor effects with the anti-PD-1 antibody. CpG-B at low doses significantly inhibited tumor growth and possessed synergistic antitumor effects with the anti-PD-1 antibody. A high dose of CpG-C was required to achieve antitumor effects comparable to those of CpG-B, which was consistent with the immunostimulatory effects in B-cell proliferation and TLR9-NF-κB activation. Importantly, CpG-C in combination with anti-PD-1 antibody inhibited tumor growth more quickly and effectively than CpG-B because CpG-B significantly upregulated PD-L1 expression on multiple host immune cells to promote tumor immune escape. Moreover, co-therapy increased the infiltration of effector memory T cells. In summary, CpG-B and CpG-C with different optimal concentrations possessed strong antitumor effects, while CpG-C was more rapid and effective for co-therapy with the anti-PD-1 antibody.

• Authors: Tete Li, Cong Hua, Wenjun Yue, Jing Wu, Xinping Lv, Qiuyu Wei, Shan Zhu, Guoxia Zang, Jiuwei Cui, Yong-Jun Liu, Jingtao Chen
• Journal: Pharmacological research (Pharmacol Res) Vol. 161 Pg. 105293 (11 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 33176206 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Immune Checkpoint Inhibitors
• Oligodeoxyribonucleotides
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Tlr9 protein, mouse
• Toll-Like Receptor 9

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• B-Lymphocytes (drug effects, immunology, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, immunology, metabolism, pathology)
• CpG Islands
• Dendritic Cells (drug effects, immunology, metabolism)
• Drug Synergism
• Female
• Immune Checkpoint Inhibitors (pharmacology)
• Lymphocyte Activation (drug effects)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Oligodeoxyribonucleotides (pharmacology)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology, metabolism)
• Signal Transduction
• Toll-Like Receptor 9 (antagonists & inhibitors, immunology, metabolism)
• Tumor Burden (drug effects)
• Tumor Escape (drug effects)
• Tumor Microenvironment