Key Laboratory for Precision Diagnosis and Treatment of Pediatric Digestive System Diseases, Endoscopy Center and Gastroenterology Department, Shenzhen Children's Hospital, Shenzhen 518036, China.
ACS Biomater Sci Eng. 2022 Nov 14;8(11):4819-4826. doi: 10.1021/acsbiomaterials.2c00639. Epub 2022 Oct 7.
Liver cancer cells evade immune surveillance and anticancer response through various pathways, including the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immune checkpoint axis that exhausts CD8 T cells. Inhibitors or antibodies of the PD-L1/PD-1 signaling axis are considered promising drugs for cancer immunotherapy and exhibit favorable clinical responses. However, adverse effects, immune tolerance, and delivery barriers of most patients limit the clinical application of PD-L1/PD-1 antibodies. Thus, it is critical to develop a novel delivery strategy to enhance anticancer immunotherapy. In this study, we bioengineered cell membrane-derived nanovesicles (NVs) presenting PD-1 proteins and dibenzocyclooctyne (DBCO) to encapsulate 1-methyltryptophan (1-MT) (DBCO+PD-1@1-MT NVs). DBCO can specifically interact with -azidoacetylmannosamine-tetraacetylate (AcManN) labeled onto metabolic cells for targeted killing of cancers. We next explored the effects of DBCO+PD-1@1-MT NVs on anticancer Hepa1-6 cells in vitro and in vivo. Results showed that PD-1@1-MT NVs dramatically inhibited Hepa1-6 proliferation, promoted peripheral blood mononuclear cell (PBMC) expansion, and strengthened anticancer therapy via blockading the PD-1/PD-L1 immune checkpoint axis, owing to the 1-methyltryptophan (1-MT) enhancement of anticancer immunotherapy efficacy through suppressing the activity of indoleamine 2,3-dioxygenase (IDO). Thus, 1-MT was encapsulated into PD-1 NVs to synergistically enhance cancer immunotherapy. Results have shown that PD-1@1-MT NVs obviously attenuated tumor growth, promoting IFN-γ production, increasing the T cells infiltration in tumors and spleens, and improving the survival period of tumor-bearing mice compared to monotherapy. Therefore, we propose a promising delivery strategy of the combination of DBCO+PD-1 NVs and 1-MT for specific and effective cancer-targeted immunotherapy.
肝癌细胞通过多种途径逃避免疫监视和抗癌反应，包括程序性死亡配体 1（PD-L1）/程序性死亡-1（PD-1）免疫检查点轴，该轴耗尽 CD8 T 细胞。PD-L1/PD-1 信号轴的抑制剂或抗体被认为是癌症免疫治疗的有前途的药物，并表现出良好的临床反应。然而，大多数患者的不良反应、免疫耐受和输送障碍限制了 PD-L1/PD-1 抗体的临床应用。因此，开发一种新的输送策略来增强抗癌免疫治疗至关重要。在这项研究中，我们生物工程化了细胞膜衍生的纳米囊泡（NVs），使其表面呈现 PD-1 蛋白和二苯并环辛炔（DBCO），以包裹 1-甲基色氨酸（1-MT）（DBCO+PD-1@1-MT NVs）。DBCO 可以特异性地与代谢细胞上标记的叠氮乙酰基甘露糖四乙酸（AcManN）相互作用，用于靶向杀伤癌症。接下来，我们研究了 DBCO+PD-1@1-MT NVs 对体外和体内 Hepa1-6 癌细胞的影响。结果表明，PD-1@1-MT NVs 通过阻断 PD-1/PD-L1 免疫检查点轴，显著抑制 Hepa1-6 细胞的增殖，促进外周血单核细胞（PBMC）的扩增，并通过 1-甲基色氨酸（1-MT）增强抗癌免疫治疗效果，增强抗癌治疗效果，因为 1-MT 通过抑制吲哚胺 2,3-双加氧酶（IDO）的活性。因此，1-MT 被包裹到 PD-1 NVs 中，以协同增强癌症免疫治疗。结果表明，与单药治疗相比，PD-1@1-MT NVs 明显减弱肿瘤生长，促进 IFN-γ 产生，增加肿瘤和脾脏中 T 细胞浸润，并延长荷瘤小鼠的生存时间。因此，我们提出了一种有前途的 DBCO+PD-1 NVs 和 1-MT 联合治疗的输送策略，用于特异性和有效的癌症靶向免疫治疗。
