PEGylated graphene oxide-mediated stimulation of vascular endothelial cells and responsive release of PD-1/PD-L1 inhibitor for efficient chemo-immunotherapy against cancer

Immune checkpoint blockade (ICB) has emerged as a promising immunotherapeutic modality against cancer in the clinic. However, only 10–30% of patients respond to ICB, primarily due to poor immunogenicity and insufficient T cell infiltration in solid tumors. Herein, we presented an approach for high-performance cancer treatment using the programmed cell death protein-1 and programmed cell death ligand-1 (PD-1/PD-L1) inhibitor (BMS-202)-loaded PEGylated graphene oxide (GPi). On the one hand, GPi dissociated tight junctions of vascular endothelial cells (VECs) in tumor, thus promoting the extravasation and intratumoral accumulation of liposomal doxorubicin (LipDox), which then effectively induced immunogenic cell death of tumor cells. On the other hand, GPi also stimulated VECs to upregulate the expression of cell-cell interaction molecules, such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, which facilitated the infiltration of T cells in tumor. Beyond acting as a stimulator of VECs, GPi could exert responsive release of BMS-202 under the acidic tumor microenvironment and blockade PD-1/PD-L1 axis in tumors. Finally, the alternating administration of GPi and LipDox effectively inhibited tumor growth in a 4T1 tumor model, providing a novel treatment mode for chemo-immunotherapy.

免疫检查点阻断（immune checkpoint blockade, ICB）已成为临床中极具潜力的癌症免疫治疗手段。然而仅10%至30%的患者可对ICB治疗产生应答，这主要源于实体瘤（solid tumors）较差的免疫原性（immunogenicity）以及肿瘤内T细胞浸润（T cell infiltration）不足。本研究报道了一种基于负载程序性死亡蛋白-1与程序性死亡配体-1（PD-1/PD-L1）抑制剂BMS-202的聚乙二醇化氧化石墨烯（GPi）的高性能癌症治疗策略。一方面，GPi可解离肿瘤内血管内皮细胞（vascular endothelial cells, VECs）的紧密连接，进而促进脂质体阿霉素（liposomal doxorubicin, LipDox）的外渗与瘤内蓄积，后者可有效诱导肿瘤细胞发生免疫原性细胞死亡（immunogenic cell death）。另一方面，GPi还可刺激血管内皮细胞上调细胞间黏附分子-1与血管细胞黏附分子-1等细胞间相互作用分子的表达，从而促进T细胞向肿瘤组织内浸润。除作为血管内皮细胞激活剂外，GPi还可在酸性肿瘤微环境（acidic tumor microenvironment）中响应性释放BMS-202，阻断肿瘤内的PD-1/PD-L1信号轴。最终，GPi与脂质体阿霉素的交替给药方案可有效抑制4T1肿瘤模型的肿瘤生长，为化学免疫治疗（chemo-immunotherapy）提供了全新的治疗模式。