Self-assembly nanovaccine containing TLR7/8 agonist and STAT3 inhibitor enhances tumor immunotherapy by augmenting tumor-specific immune response.
Self-assembly nanovaccine containing TLR7/8 agonist and STAT3 inhibitor enhances tumor immunotherapy by augmenting tumor-specific immune response.
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含有TLR7/8激动剂和STAT3抑制剂的自组装纳米疫苗通过增强肿瘤特异性免疫反应来增强肿瘤免疫治疗
DOI：
10.1136/jitc-2021-003132
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发表时间：
2021-08
影响因子：
10.9
通讯作者：
Qiao Y
中科院分区：
文献类型：
--
作者：
Zhang L;Huang J;Chen X;Pan C;He Y;Su R;Guo D;Yin S;Wang S;Zhou L;Chen J;Zheng S;Qiao Y
背景癌症疫苗是一种很有前途的癌症免疫治疗策略。癌症疫苗激发针对肿瘤抗原的特异性细胞毒性免疫应答。然而，传统的基于肽的癌症疫苗的功效是有限的，这是由于抗原和佐剂向树突状细胞（DC）的低效递送。因此，有必要开发一种新的合理设计的癌症疫苗，以最大限度地发挥其预期效果。方法采用不饱和脂肪酸二十二碳六烯酸（DHA）结合抗原和Toll样受体7/8激动剂R848包封信号转导和转录激活因子3（STATIC）抑制剂STATIC，构建自组装无载体多组分抗肿瘤纳米疫苗（SVMAV）。研究了SVMAV的特性。通过体外分析检测SVMAV促进DC功能的能力。在体内研究了SVMAV及其与抗程序性细胞死亡蛋白1抗体（aPD-1）的组合的抗肿瘤作用。在原位肝细胞癌模型中检查SVMAV用于新抗原靶向的个性化癌症疫苗的潜在应用。结果SVMAV与R848和STATIC同时转染，可有效地迁移至淋巴结，并通过促进DC对抗原的摄取、刺激DC成熟、增强抗原交叉递呈等途径激活CD 8 + T细胞，发挥新抗原特异性杀伤作用。SVMAV不仅对原发性黑色素瘤移植物具有较强的抗肿瘤作用，而且对肺转移瘤具有保护作用。此外，SVMAV和aPD-1的联合治疗发挥协同抗肿瘤活性，并延长荷黑色素瘤小鼠的存活时间。值得注意的是，根据预测的Hepa 1 -6细胞的新抗原设计了基于细胞系特异性新抗原的SVMAV，以检查SVMAV用于个性化癌症疫苗的潜在应用。令人鼓舞的是，在用Hepa 1 -6细胞建立的原位肝细胞癌模型中，新抗原特异性SVMAV实现了比aPD-1更强的抗肿瘤活性。结论本研究为肿瘤免疫治疗过程中新抗原和免疫调节化合物的联合递送提供了一个有效的平台。
Background Cancer vaccines are a promising strategy for cancer immunotherapy. Cancer vaccines elicits a specific cytotoxic immune response to tumor antigens. However, the efficacy of traditional peptide-based cancer vaccines is limited due to the inefficient delivery of antigens and adjuvants to dendritic cells (DCs). Therefore, it is necessary to develop a novel rationally designed cancer vaccine to maximize its desired effects. Methods A Self-assembling Vehicle-free Multi-component Antitumor nanoVaccine (SVMAV) was constructed by using an unsaturated fatty acid docosahexaenoic acid (DHA)-conjugated antigen and R848 (a Toll-like receptor 7/8 agonist) to encapsulate stattic (a signal transducer and activator of transcription 3 inhibitor). The characteristics of SVMAV were investigated. The ability of SVMAV to promote DC functions was examined by in vitro analysis. The antitumor effects of SVMAV and its combination with antiprogrammed cell death protein 1 antibody (aPD-1) were also investigated in vivo. The potential application of SVMAV for neoantigen-targeted, personalized cancer vaccines was examined in an orthotopic hepatocellular carcinoma model. Results The obtained SVMAV efficiently migrated into lymph nodes and primed CD8+ T cells for exert neoantigen-specific killing by promoting the antigen uptake by DCs, stimulating DC maturation, and enhancing antigen cross-presentation, due to the simultaneous delivery of the antigen, R848 and stattic. SVMAV could not only yield a robust antitumor effect for primary melanoma allografts, but also exert a protective effect for lung metastases. Moreover, combination treatment of SVMAV and aPD-1 exerted synergistic antitumor activity and extended the survival duration of melanoma-bearing mice. Notably, a cell line-specific neoantigen-based SVMAV was designed according to predicted neoantigens for Hepa1-6 cells to examine the potential application of SVMAV for personalized cancer vaccine. Encouragingly, neoantigen-specific SVMAV achieved stronger antitumor activity than aPD-1 in an orthotopic hepatocellular cancer model established with Hepa1-6 cells. Conclusions In summary, this study offers an efficient codelivery platform for neoantigens and immunoregulatory compounds to enhance immune responses during cancer immune therapy.
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DOI：
10.1038/nrc3258
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Cohen, Cyrille J.;Gartner, Jared J.;Robbins, Paul F.
通讯作者：
Robbins, Paul F.
影响因子：
4.4
作者：
Park, SJ;Nakagawa, T;Hirano, T
通讯作者：
Hirano, T
癌症免疫疗法。树突状细胞疫苗增加了黑色素瘤新抗原特异性T细胞的广度和多样性。
DOI：
10.1126/science.aaa3828
发表时间：
2015-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carreno BM;Magrini V;Becker-Hapak M;Kaabinejadian S;Hundal J;Petti AA;Ly A;Lie WR;Hildebrand WH;Mardis ER;Linette GP
通讯作者：
Linette GP
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G