武汉大学张先正团队开发了一种基于AspPheTyr三肽酶促聚合反应的肿瘤免疫治疗策略。 相关成果发表在2021年3月25日出版的《美国化学会杂志》。

免疫治疗为癌症的治疗提供了一种很有前途的策略。然而，即使在抗原负荷较高的肿瘤中，系统性抑制抗原提呈仍然极大地限制了免疫治疗的应用。

该文中，研究人员构建了一个基于功能性三肽Asp-Phe-Tyr（DFY）的肿瘤蛋白工程系统，该系统能够自动收集并将免疫基因肿瘤蛋白从靶细胞传递到免疫细胞。通过酪氨酸酶催化聚合，DFY三肽选择性地聚集在酪氨酸酶高表达的黑色素瘤细胞中。然后通过Michael加成将富含醌的中间体与肿瘤特异性蛋白共价连接，形成携带肿瘤蛋白的微纤维，这些微纤维可以被抗原呈递细胞吞噬，并表现出增强免疫效果的肿瘤抗原特性。

在抗原呈递不足的黑色素瘤细胞中，该系统可以成功地富集并将含有肿瘤抗原的蛋白质转运到免疫细胞。此外，在小鼠黑色素瘤的体内研究中，DFY三肽经皮给药抑制肿瘤生长和术后复发。

该发现为利用化学生物学的某些聚合反应来调节机体的免疫系统提供了一条途径。

附：英文原文

Title: A Strategy Based on the Enzyme-Catalyzed Polymerization Reaction of Asp-Phe-Tyr Tripeptide for Cancer Immunotherapy

Author: Qiu-Ling Zhang, Diwei Zheng, Xue Dong, Pei Pan, Si-Min Zeng, Fan Gao, Si-Xue Cheng, Xian-Zheng Zhang

Issue&Volume: March 25, 2021

Abstract: Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.

DOI: 10.1021/jacs.1c00945

Source: https://pubs.acs.org/doi/10.1021/jacs.1c00945