Fully Synthetic Invariant NKT Cell-Dependent Self-Adjuvanting Antitumor Vaccines Eliciting Potent Immune Response in Mice.,Molecular Pharmaceutics

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Fully Synthetic Invariant NKT Cell-Dependent Self-Adjuvanting Antitumor Vaccines Eliciting Potent Immune Response in Mice.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-12-31 , DOI: 10.1021/acs.molpharmaceut.9b00720
Pu-Guang Chen ₁ , Hong-Guo Hu ₁ , Zhan-Yi Sun ₁ , Qian-Qian Li ₁ , Bo-Dou Zhang ₁ , Jun-Jun Wu ₁ , Wen-Hao Li ₁ , Yu-Fen Zhao ₁ , Yong-Xiang Chen ₁ , Yan-Mei Li _{1,

2}

Affiliation

Constructing an effective therapeutic cancer vaccine is very attractive and promising for cancer immunotherapy. However, the poor immunogenicity of tumor antigens and suppression of the immune system in the tumor microenvironment are two major obstacles for developing effective cancer vaccines. Invariant NKT cells (iNKT cells), which are essential bridges between the innate and adaptive immune systems, can be rapidly activated by their agonists and, consequently, evoke whole immune systems. Herein, we conjugated a potent agonist of the iNKT cell, α-galactosylceramide (α-GalCer), with the tumor-associated MUC1 glycopeptide antigens as novel self-adjuvanting cancer vaccines through click chemistry. Immunological studies revealed that the mouse immune system was potently evoked and that high levels of tumor-specific IgG antibodies were elicited by vaccine conjugates without an external adjuvant. The produced antibodies could specifically recognize and bind to antigen-expressing cancer cells and, subsequently, induce cytotoxicity through complement-dependent cytotoxicity. Thus, the insertion of α-GalCer significantly improved the immunogenicity of the MUC1 glycopeptide and induced strong antigen-specific antitumor responses, indicating that α-GalCer is an effective built-in adjuvant for constructing potent chemical synthetic antitumor vaccines.

中文翻译：

完全合成不变的NKT细胞依赖性自佐剂抗肿瘤疫苗，可增强小鼠的免疫反应。

构建有效的治疗性癌症疫苗对于癌症免疫治疗非常有吸引力，并且很有希望。然而，肿瘤抗原的不良免疫原性和肿瘤微环境中免疫系统的抑制是开发有效的癌症疫苗的两个主要障碍。不变的NKT细胞（iNKT细胞）是先天性和适应性免疫系统之间的重要桥梁，它们的激动剂可以迅速激活它们，从而唤起整个免疫系统。在本文中，我们通过点击化学将iNKT细胞的强效激动剂α-半乳糖基神经酰胺（α-GalCer）与肿瘤相关的MUC1糖肽抗原缀合在一起，作为新型的自我佐治性癌症疫苗。免疫学研究表明，小鼠免疫系统被有效诱发，而没有外部佐剂的疫苗结合物可引发高水平的肿瘤特异性IgG抗体。产生的抗体可以特异性识别并与表达抗原的癌细胞结合，随后通过补体依赖性细胞毒性诱导细胞毒性。因此，α-GalCer的插入显着改善了MUC1糖肽的免疫原性并诱导了强烈的抗原特异性抗肿瘤反应，表明α-GalCer是构建有效的化学合成抗肿瘤疫苗的有效内置佐剂。通过补体依赖性细胞毒性诱导细胞毒性。因此，插入α-GalCer可以显着提高MUC1糖肽的免疫原性并诱导强烈的抗原特异性抗肿瘤反应，这表明α-GalCer是构建有效的化学合成抗肿瘤疫苗的有效内置佐剂。通过补体依赖性细胞毒性诱导细胞毒性。因此，插入α-GalCer可以显着提高MUC1糖肽的免疫原性并诱导强烈的抗原特异性抗肿瘤反应，这表明α-GalCer是构建有效的化学合成抗肿瘤疫苗的有效内置佐剂。

更新日期：2019-12-31

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