PDF(Pubmed)
Abstract：
Synergistic immunotherapy of immune checkpoint blockade (ICB) and immunogenic cell death (ICD) has shown remarkable therapeutic efficacy in various cancers. However, patients show low response rates and undesirable outcomes to these combination therapies owing to the recycling mechanism of programmed death-ligand 1 (PD-L1) and the systemic toxicity of ICD-inducing chemotherapeutic drugs. Herein, we propose all-in-one glycol chitosan nanoparticles (CNPs) that can deliver anti-PD-L1 peptide (PP) and doxorubicin (DOX) to targeted tumor tissues for a safe and more effective synergistic immunotherapy. The PP-CNPs, which are prepared by conjugating ᴅ-form PP (NYSKPTDRQYHF) to CNPs, form stable nanoparticles that promote multivalent binding with PD-L1 proteins on the targeted tumor cell surface, resulting in effective lysosomal PD-L1 degradation in contrast with anti-PD-L1 antibody, which induces recycling of endocytosed PD-L1. Consequently, PP-CNPs prevent subcellular PD-L1 recycling and eventually destruct immune escape mechanism in CT26 colon tumor-bearing mice. Moreover, the ICD inducer, DOX is loaded into PP-CNPs (DOX-PP-CNPs) for synergistic ICD and ICB therapy, inducing a large number of damage-associated molecular patterns (DAMPs) in targeted tumor tissues with minimal toxicity in normal tissues. When the DOX-PP-CNPs are intravenously injected into CT26 colon tumor-bearing mice, PP and DOX are efficiently delivered to the tumor tissues via nanoparticle-derived passive and active targeting, which eventually induce both lysosomal PD-L1 degradation and substantial ICD, resulting in a high rate of complete tumor regression (CR: 60%) by a strong antitumor immune response. Collectively, this study demonstrates the superior efficacy of synergistic immunotherapy using all-in-one nanoparticles to deliver PP and DOX to targeted tumor tissues.
摘要：
免疫检查点阻断(ICB)和免疫原性细胞死亡(ICD)的协同免疫疗法在各种癌症中显示出显著的治疗功效。然而,由于程序性死亡-配体1(PD-L1)的再循环机制和诱导ICD的化疗药物的全身毒性,患者对这些联合治疗的应答率和不良结局较低.在这里，我们提出了多合一乙二醇壳聚糖纳米颗粒(CNPs),该纳米颗粒可将抗PD-L1肽(PP)和多柔比星(DOX)递送至靶向肿瘤组织,以实现安全和更有效的协同免疫疗法.PP-CNPs,通过将α-形式PP（NYSKPTDRQYHF）与CNPs缀合制备，形成稳定的纳米颗粒，促进与靶向肿瘤细胞表面PD-L1蛋白的多价结合，与抗PD-L1抗体相比，导致有效的溶酶体PD-L1降解，诱导内吞PD-L1的再循环。因此,PP-CNP阻止CT26结肠荷瘤小鼠亚细胞PD-L1再循环并最终破坏免疫逃逸机制。此外，ICD诱导器,将DOX加载到PP-CNPs（DOX-PP-CNPs）中，用于协同ICD和ICB治疗，在目标肿瘤组织中诱导大量损伤相关分子模式（DAMPs），在正常组织中毒性最小。当DOX-PP-CNPs静脉注射到CT26结肠荷瘤小鼠体内时，PP和DOX通过纳米粒子衍生的被动和主动靶向有效地递送到肿瘤组织，最终诱导溶酶体PD-L1降解和大量ICD，通过强烈的抗肿瘤免疫应答导致肿瘤完全消退的高比率(CR:60%)。总的来说，这项研究证明了使用多合一纳米颗粒将PP和DOX递送至靶向肿瘤组织的协同免疫疗法的优异疗效.
