STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation.
STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation.
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DOI：
10.1007/s12274-022-4282-x
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发表时间：
2022
期刊：
影响因子：
9.9
通讯作者：
中科院分区：
文献类型：
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作者：
基于模式识别受体（PRR）的免疫刺激疗法已经成为对抗癌症的有效方法，具有在低免疫原性肿瘤环境中募集肿瘤特异性淋巴细胞的能力。干扰素基因刺激因子（stimulator of interferon gene，STING）的激动剂环二核苷酸（cyclic dinucleotides，CDN）是一类非常有前途的抗肿瘤分子，通过激活天然免疫增强肿瘤免疫原性。然而，CDN的肿瘤免疫功效受到几个因素的限制，包括相对狭窄的细胞因子产生、低效的STING递送和快速清除。此外，单一佐剂分子无法引发广泛的细胞因子反应，因此无法进一步增强抗癌作用。为了解决这个问题，两种或更多种激动剂分子通常一起使用以协同增强免疫功效。在这项工作中，我们发现STING激动剂CDGSF和Toll样受体7/8（TLR7/8）激动剂522的组合产生了更广泛的细胞因子应答。随后，我们开发了多组分纳米疫苗（MCNV），其由PC7A聚合物作为包封抗原OVA和佐剂分子的纳米载体组成。这些MCNV激活骨髓来源的树突状细胞（BMDC）以产生多种促炎因子，这些促炎因子促进抗原交叉呈递以刺激特异性抗肿瘤T细胞应答。在体内实验中，我们观察到MCNV在肿瘤浸润淋巴细胞中引发了强烈的T细胞反应，导致显著的肿瘤消退，特别是在没有其他合作疗法的情况下，小鼠在25天内的存活率为100%。这些数据表明，我们的纳米疫苗具有很大的潜力，可以提高癌症免疫治疗的持久性和效力。补充材料（CDGSF、522、PC7A和OVA的合成; MCNV的制备;流式细胞术的代表性设门策略）可在本文的在线版本10.1007/s12274 - 022 - 4282-x中获得。
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. Supplementary material (synthesis of CDGSF, 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.
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DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
4.9
作者：
Collier MA;Junkins RD;Gallovic MD;Johnson BM;Johnson MM;Macintyre AN;Sempowski GD;Bachelder EM;Ting JP;Ainslie KM
通讯作者：
Ainslie KM
影响因子：
2.8
作者：
Cai, Hui;Huang, Zhi-Hua;Li, Yan-Mei
通讯作者：
Li, Yan-Mei
影响因子：
15.9
作者：
Hanson, Melissa C.;Crespo, Monica R.;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.