S-540956, a CpG Oligonucleotide Annealed to a Complementary Strand With an Amphiphilic Chain Unit, Acts as a Potent Cancer Vaccine Adjuvant by Targeting Draining Lymph Nodes

• Published in: Frontiers in immunology Vol. 12; p. 803090
• Main Authors: Nakagawa, Takayuki, Tanino, Tetsuya, Onishi, Motoyasu, Tofukuji, Soichi, Kanazawa, Takayuki, Ishioka, Yukichi, Itoh, Takeshi, Kugimiya, Akira, Katayama, Kazufumi, Yamamoto, Takuya, Nagira, Morio, Ishii, Ken J.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.12.2021
• Subjects: adjuvant; Adjuvants, Vaccine - chemistry; Adjuvants, Vaccine - therapeutic use; Animals; cancer peptide vaccine; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; CpG oligonucleotide; delivery system; Dendritic Cells - immunology; DNA - chemistry; draining lymph node; Female; Humans; Immunization; Immunology; Lung Neoplasms - immunology; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - chemistry; Papillomavirus E7 Proteins - immunology; Sentinel Lymph Node - immunology; Surface-Active Agents - chemistry; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; Vaccines, Subunit; CpG oligonucleotide; delivery system; adjuvant; cancer peptide vaccine; draining lymph node
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.803090

Robust induction of cancer-antigen-specific CD8 + T cells is essential for the success of cancer peptide vaccines, which are composed of a peptide derived from a cancer-specific antigen and an immune-potentiating adjuvant, such as a Toll-like receptor (TLR) agonist. Efficient delivery of a vaccine antigen and an adjuvant to antigen-presenting cells in the draining lymph nodes (LNs) holds key to maximize vaccine efficacy. Here, we developed S-540956, a novel TLR9-agonistic adjuvant consisting of B-type CpG ODN2006 (also known as CpG7909), annealed to its complementary sequence oligodeoxynucleotide (ODN) conjugated to a lipid; it could target both a cancer peptide antigen and a CpG-adjuvant in the draining LNs. S-540956 accumulation in the draining LNs and activation of plasmacytoid dendritic cells (pDCs) were significantly higher than that of ODN2006. Mechanistic analysis revealed that S-540956 enhanced the induction of MHC class I peptide-specific CD8 + T cell responses via TLR9 in a CD4 + T cell-independent manner. In mice, the therapeutic effect of S-540956-adjuvanted with a human papillomavirus (HPV)-E7 peptide vaccine against HPV-E7-expressing TC-1 tumors was significantly better than that of an ODN2006-adjuvanted vaccine. Our findings demonstrate a novel adjuvant discovery with the complementary strand conjugated to a lipid, which enabled draining LN targeting and increased ODN2006 accumulation in draining LNs, thereby enhancing the adjuvant effect. Our findings imply that S-540956 is a promising adjuvant for cancer peptide vaccines and has a high potential for applications in various vaccines, including recombinant protein vaccines.