Tianjin University of Science and Technology, Tianjin 300457, China; Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China.
Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen 518055, China; Department of Radiation Oncology, Ningbo No.2 Hospital, Ningbo, Zhejiang 315010, China.
Bioorg Med Chem Lett. 2024 Nov 1;112:129945. doi: 10.1016/j.bmcl.2024.129945. Epub 2024 Aug 31.
Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in cancer immunotherapy.
调节性 T（Treg）细胞在免疫稳态中发挥核心作用。叉头框 P3（Foxp3）是 Treg 细胞的标志性分子，是其发育和功能的关键转录因子。研究表明，Foxp3 的降解可以在实现有效的抗肿瘤免疫方面提供治疗益处。在这项研究中，我们基于 Foxp3 的 15 肽抑制剂（P60）设计了三种 PROTAC 分子，即 P60-L1-VHL、P60-L2-VHL 和 P60-L3-VHL，并探索了它们在调节 Foxp3 表达和功能方面的潜力。我们的数据表明，在这些分子中，P60-L3-VHL 可以分别抑制 HEK 293T 和 HeLa 细胞中 Foxp3 的表达和核定位。同时，在 P60-L3-VHL 处理的细胞中使用蛋白酶体抑制剂会导致 Foxp3 表达增加，表明 P60-L3-VHL 通过其在蛋白酶体途径中的降解来介导 Foxp3 的抑制。我们进一步证实，P60-L3-VHL 减少了体外激活的 Treg 细胞的分化和 Foxp3 的表达。总的来说，我们的研究结果表明，P60-L3-VHL 通过降解 Foxp3 抑制 Treg 细胞的分化，这可能对癌症免疫治疗具有潜在意义。
