iRGD synergizes with PD-1 knockout immunotherapy by enhancing lymphocyte infiltration in gastric cancer
iRGD synergizes with PD-1 knockout immunotherapy by enhancing lymphocyte infiltration in gastric cancer
复制标题
iRGD 通过增强胃癌淋巴细胞浸润与 PD-1 敲除免疫疗法产生协同作用
DOI：
10.1038/s41467-019-09296-6
复制
发表时间：
2019-03-22
影响因子：
16.6
通讯作者：
Liu, Baorui
中科院分区：
文献类型：
--
作者：
Ding, Naiqing;Zou, Zhengyun;Liu, Baorui
活化淋巴细胞对肿瘤浸润不良是限制过继细胞免疫治疗效果的根本因素。肿瘤穿透肽iRGD已被广泛用于将药物输送到肿瘤组织中。在这项研究中，我们首次证明了iRGD也可以促进淋巴细胞在3D肿瘤球体和几种异种移植小鼠模型中的浸润。此外，将iRGD修饰与PD-1敲除淋巴细胞结合，显示出优越的抗肿瘤效率。机制研究表明，iRGD与neuropilin-1结合导致内皮屏障调节剂VE-cadherin酪氨酸磷酸化，其在打开内皮细胞接触和促进跨内皮淋巴细胞迁移中起作用。综上所述，这些结果表明，iRGD修饰可以促进肿瘤特异性淋巴细胞浸润，从而克服实体瘤过继免疫细胞治疗相关的瓶颈。
Poor infiltration of activated lymphocytes into tumors represents a fundamental factor limiting the therapeutic effect of adoptive cell immunotherapy. A tumor-penetrating peptide, iRGD, has been widely used to deliver drugs into tumor tissues. In this study, we demonstrate for the first time that iRGD could also facilitate the infiltration of lymphocytes in both 3D tumor spheroids and several xenograft mouse models. In addition, combining iRGD modification with PD-1 knockout lymphocytes reveals a superior anti-tumor efficiency. Mechanistic studies demonstrate that the binding of iRGD to neuropilin-1 results in tyrosine phosphorylation of the endothelial barrier regulator VE-cadherin, which plays a role in the opening of endothelial cell contacts and the promotion of transendothelial lymphocyte migration. In summary, these results demonstrate that iRGD modification could promote tumor-specific lymphocyte infiltration, and thereby overcome the bottleneck associated with adoptive immune cell therapy in solid tumors.