College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China.
School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
J Control Release. 2023 Sep;361:681-693. doi: 10.1016/j.jconrel.2023.08.033. Epub 2023 Aug 19.
The two-signal model of T cell activation has helped shape our understanding of the adaptive immune response for over four decades. According to the model, activation of T cells requires a stimulus through the T cell receptor/CD3 complex (signal 1) and a costimulatory signal 2. Stimulation of activatory signals via T cell agonists has thus emerged. However, for a robust T cell activation, it necessitates not only the presence of both signal 1 and signal 2, but also a high signaling strength. Herein, we report a photo-activable nano-agonist for the two-signal model of T cell in vivo activation. A UV-crosslinkable polymer is coated onto upconversion nanoparticles with satisfactory NIR-to-UV light conversion efficiency. Then dual signal molecules, i.e., signal 1 and signal 2, are conjugated to the polymer end to yield the photo-activable T cell nano-agonist. In melanoma and breast cancer models, photo-activable nano-agonist could bind onto corresponding activatory receptors on the surface of T cells, but has limited activity without the application of NIR light (absence of photo-crosslinking of receptors and consequently a poor signaling strength). While when the NIR light is switched on locally, T cells in tumor are remarkably activated and kill tumor cells effectively. Moreover, we do not observe any detectable toxicities related to the photo-activable nano-agonist. We believe with two activatory signals being simultaneously strengthened by local photo-switched crosslinking, T cells realize a robust and selective activation in tumor and, consequently contribute to an enhanced and safe tumor immunotherapy.
双信号模型在过去四十多年来帮助我们理解适应性免疫反应。根据该模型，T 细胞的激活需要通过 T 细胞受体/CD3 复合物（信号 1）和共刺激信号 2 进行刺激。因此，已经出现了通过 T 细胞激动剂刺激激活信号的方法。然而，为了实现强大的 T 细胞激活，不仅需要存在信号 1 和信号 2，还需要高强度的信号。在此，我们报告了一种用于体内 T 细胞双信号模型激活的光可激活纳米激动剂。将可交联的聚合物涂覆在具有令人满意的近红外到紫外光转换效率的上转换纳米颗粒上。然后，将双信号分子，即信号 1 和信号 2，连接到聚合物末端，得到光可激活的 T 细胞纳米激动剂。在黑色素瘤和乳腺癌模型中，光可激活的纳米激动剂可以结合到 T 细胞表面的相应激活受体上，但在没有近红外光应用的情况下（缺乏受体的光交联，因此信号强度差），其活性有限。然而，当局部开启近红外光时，肿瘤中的 T 细胞被显著激活，并有效地杀死肿瘤细胞。此外，我们没有观察到与光可激活的纳米激动剂相关的任何可检测的毒性。我们相信，通过局部光开关交联同时增强两个激活信号，T 细胞在肿瘤中实现了强大而选择性的激活，从而促进了增强和安全的肿瘤免疫治疗。
