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Nano Research 2022, 15(7): 6328-6339 https://doi.org/10.1007/s12274-022-4282-x
Research Article | Issue | Published: 18 April 2022

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

Show Author's Information Bo-Dou Zhang1,  Jun-Jun Wu1,  Wen-Hao Li1,  Hong-Guo Hu1,  Lang Zhao1,  Pei-Yang He1,  Yu-Fen Zhao1,3,  Yan-Mei Li1,2( )
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
Beijing Institute for Brain Disorders, Beijing 100069, China
Institute of Drug Discovery Technology, Ningbo University, Ningbo 315201, China
Keywords:
lymph node targeting, nanovaccines, stimulator of interferon gene (STING), Toll-like receptor 7/8, synergistic immune activation
Topics:
Vaccines
Cite this article:
Zhang B-D, Wu J-J, Li W-H, et al. STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation. Nano Research, 2022, 15(7): 6328-6339. https://doi.org/10.1007/s12274-022-4282-x
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Abstract Full text Electronic supplementary material About this article

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 CDGSF 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.


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Electronic supplementary material
About this article

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

Show Author's information Bo-Dou Zhang1, Jun-Jun Wu1, Wen-Hao Li1, Hong-Guo Hu1, Lang Zhao1, Pei-Yang He1, Yu-Fen Zhao1,3, Yan-Mei Li1,2( )
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
Beijing Institute for Brain Disorders, Beijing 100069, China
Institute of Drug Discovery Technology, Ningbo University, Ningbo 315201, 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 CDGSF 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.

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

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Publication history
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Acknowledgements

Publication history

Received: 27 December 2021
Revised: 28 February 2022
Accepted: 01 March 2022
Published: 18 April 2022
Issue date: July 2022

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

This work was supported by the National Key R&D Program of China (Nos. 2019YFA0904200 and 2018YFA0507600), Tsinghua University Spring Breeze Fund (No. 2020Z99CFY042), and the National Natural Science Foundation of China (No. 92053108).

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