通过肿瘤选择性血栓形成,积极招募抗PD-1结合血小板,以增强抗癌免疫治疗。
Active recruitment of anti-PD-1-conjugated platelets through tumor-selective thrombosis for enhanced anticancer immunotherapy.
发表日期:2023 Mar 29
作者:
Yixin Wang, Wen Li, Zhaoting Li, Fanyi Mo, Yu Chen, Mari Iida, Deric L Wheeler, Quanyin Hu
来源:
Immunity & Ageing
摘要:
免疫检查点抑制剂(ICIs)可使T细胞重振活力,清除肿瘤细胞,在抗击各种类型的肿瘤方面表现出巨大的潜力。我们提出了一个输送策略,以增强肿瘤选择性ICI积累,利用血小板及其衍生物对凝血级联信号的响应能力。融合蛋白tTF-RGD瞄准肿瘤血管生成的血管内皮细胞,在肿瘤部位局部启动凝血,形成“细胞蜂巢”,招募抗PD-1抗体(aPD-1)偶联的血小板到肿瘤部位,随后激活血小板释放aPD-1抗体,重新激活T细胞,提高免疫治疗效果。此外,在患者源性异种移植乳腺癌模型上,血小板膜包裹的纳米颗粒也可以响应tTF-RGD引发的凝血信号,从而增强装载的化疗药物的积累和抗肿瘤效力。我们的研究阐明了一种多功能平台技术,利用血小板和血小板衍生物对血栓形成的响应能力,增强局部ICI和化疗药物的积累。
Immune checkpoint inhibitors (ICIs) can reinvigorate T cells to eradicate tumor cells, showing great potential in combating various types of tumors. We propose a delivery strategy to enhance tumor-selective ICI accumulation, which leverages the responsiveness of platelets and platelet-derivatives to coagulation cascade signals. A fused protein tTF-RGD targets tumor angiogenic blood vessel endothelial cells and initiates the coagulation locoregionally at the tumor site, forming a "cellular hive" to recruit anti-PD-1 antibody (aPD-1)-conjugated platelets to the tumor site and subsequently activating platelets to release aPD-1 antibody to reactivate T cells for improved immunotherapy. Moreover, on a patient-derived xenograft breast cancer model, the platelet membrane-coated nanoparticles can also respond to the coagulation signals initiated by tTF-RGD, thus enhancing the accumulation and antitumor efficacy of the loaded chemotherapeutics. Our study illustrates a versatile platform technology to enhance the local accumulation of ICIs and chemodrugs by taking advantage of the responsiveness of platelets and platelet derivatives to thrombosis.