在过去的四十年中,T细胞活化的双信号模型帮助塑造了我们对适应性免疫反应的理解。根据模型,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的刺激。因此出现了通过T细胞激动剂的激活信号的刺激。然而,对于强大的T细胞激活,这不仅需要信号1和信号2两者的存在,而且需要高信令强度。在这里,我们报道了一种可光活化的纳米激动剂,用于T细胞体内活化的双信号模型。将可UV交联的聚合物以令人满意的NIR至UV光转换效率涂覆到上转换纳米颗粒上。然后双信号分子,即,信号1和信号2与聚合物末端缀合以产生光活化的T细胞纳米激动剂。在黑色素瘤和乳腺癌模型中,光活化的纳米激动剂可以结合到T细胞表面相应的活化受体上,但是在不应用NIR光的情况下具有有限的活性(不存在受体的光交联,因此信号传导强度差)。当本地打开NIR灯时,肿瘤中的T细胞被显著激活并有效地杀死肿瘤细胞。此外,我们没有观察到任何与光活化纳米激动剂相关的可检测毒性.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和选择性的激活,因此有助于增强和安全的肿瘤免疫治疗。
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.