STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Bo-Dou Zhang; Jun-Jun Wu; Wen-Hao Li; Hong-Guo Hu; Lang Zhao; Pei-Yang He; Yu-Fen Zhao; Yan-Mei Li

doi:10.1007/s12274-022-4282-x

STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation

Nano Res. 2022;15(7):6328-6339. doi: 10.1007/s12274-022-4282-x. Epub 2022 Apr 18.

Authors

Bo-Dou Zhang¹, Jun-Jun Wu¹, Wen-Hao Li¹, Hong-Guo Hu¹, Lang Zhao¹, Pei-Yang He¹, Yu-Fen Zhao^{1

2}, Yan-Mei Li^{1

3}

Affiliations

¹ Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084 China.
² Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315201 China.
³ Beijing Institute for Brain Disorders, Beijing, 100069 China.

Abstract

Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine production, inefficient delivery to STING, and rapid clearance. In addition, a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist molecules are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDG^SF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo experiments, we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.

Electronic supplementary material: Supplementary material (synthesis of CDG^SF, 522, PC7A and OVA; preparation of MCNVs; representative gating strategies for flow cytometry) is available in the online version of this article at 10.1007/s12274-022-4282-x.

Keywords: Toll-like receptor 7/8; lymph node targeting; nanovaccines; stimulator of interferon gene (STING); synergistic immune activation.