An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8+ T Cells in Nonhuman Primates.

Abstract

The priming, boosting, and restoration of memory cytotoxic CD8+ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid-based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid-based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-α and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic-polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response-boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer.

• Authors: Yuji Masuta, Takuya Yamamoto, Yayoi Natsume-Kitatani, Tomohiro Kanuma, Eiko Moriishi, Kouji Kobiyama, Kenji Mizuguchi, Yasuhiro Yasutomi, Ken J Ishii
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 6 Pg. 2067-2075 (03 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29431693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Antigens
• Cytokines
• Lectins, C-Type
• Toll-Like Receptor 9
• dectin 1
• Sizofiran

Topics

• Animals
• Antigens (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cytokines (immunology)
• Dendritic Cells (immunology)
• Immunologic Memory (immunology)
• Immunotherapy (methods)
• Inflammation (immunology)
• Lectins, C-Type (immunology)
• Lymphocyte Activation (immunology)
• Macaca fascicularis
• Male
• Neutrophils (immunology)
• Primates
• Sizofiran (immunology)
• Toll-Like Receptor 9 (immunology)