中性粒细胞促进肺癌进展的作用机制研究及以其为药物递送载体治疗肺癌探讨

Polymorphonuclear neutrophil is the dominant subtype and consists of 55-70% of peripheral leukocytes. Elevated peripheral neutrophil count is observed in many kinds of cancer patients and associated with poor prognosis. Due to the huge amount and the ability to transmigrate through the blood vessel barrier and infiltrate into tumor tissues, increasing researchers use neutrophils as the drug delivery carrier. However, studies shown activated neutrophils promote cancer initiation, metastasis and cancer progression. Therefore, it has to put it under control before using neutrophil as a drug delivery carrier. From preliminary data, the applicant found that neutrophils were increased in lung cancer tissue as compare to control in human clinical samples. And inhibition of PARP-1 diminished neutrophil activation induced lung cancer progression. In addition, local acute injury induced by radiotherapy promoted neutrophil activation and infiltration in lung cancer tissue in mice. Simultaneously, neutrophil-targeting nanoparticles enriched in the tumor. In this proposal, we would combine neutrophil activation inhibition and neutrophil-mediated nanoparticle drug delivery to improve the efficiency for lung cancer therapy.

中性粒细胞（Polymorphonuclear Neutrophil, PMN）占白细胞总数的55-70%，肿瘤患者外周血PMN数量增加，与患者预后负相关。 基于PMN数量巨多及其能够穿越血管屏障迁移至肿瘤部位的特性，近年来以PMN为药物递送载体的研究逐渐增多，然而，大量研究表明PMN促进肿瘤发生、转移和疾病进展。因此，以PMN为药物递送载体首先要解决其自身促进肿瘤进展的问题，申请者前期研究发现肺癌组织中有大量PMN浸润，靶向抑制 PARP-1可以消除PMN对肺癌进展的促进作用；放射治疗引发的急性损伤可以激活并诱导PMN在肿瘤部位聚集，同时将纳米载体药物携带至肿瘤部位。有鉴于此，本项目主要围绕PMN促进肺癌进展的作用机制开展研究，并初步探讨以其为纳米药物投递载体治疗肺癌，以期提高肺癌治疗效果。

作为天然免疫的重要组成部分，中性粒细胞在机体的生理病理进程中发挥重要作用。越来越多的研究证实，肿瘤浸润中性粒细胞通过多种方式影响肿瘤进展。我们的研究表明肿瘤浸润中性粒细胞数量与肺癌预后负相关，一方面肺癌细胞可以诱导中性粒细胞发生N2型极化，抑制抗肿瘤免疫，促进肺癌血管生成和肿瘤生长；另一方面，肺癌细胞诱导中性粒细胞胞外陷阱生成，进一步促进T细胞耗竭，导致肺癌免疫逃逸。深入研究发现，抑制PARP-1能够阻断肺癌细胞诱导的中性粒细胞极化，消除中性粒细胞对肺癌进展的促进作用；此外，PARP-1可调控中性粒细胞活化，使中性粒细胞ROS大量生成，促进中性粒细胞胞外陷阱生成，进而诱导肿瘤浸润T细胞耗竭指标Tim3表达上调，导致T细胞凋亡增加，促进肺癌免疫逃逸。进一步，为利用中性粒细胞易浸润肿瘤的特性，我们设计合成了基于白蛋白紫杉醇的纳米药物Nab-PTX，其可被活化的中性粒细胞摄取，通过肿瘤局部放疗激活中性粒细胞，进而使其荷载静脉注射的Nab-PTX并携带至肿瘤部位，体内结果证实，放疗联合Nab-PTX使抑瘤效果提高2倍以上，且大大降低了白蛋白紫杉醇静脉给药导致的骨髓抑制等毒副作用。这些结果表明，靶向中性粒细胞可能为提高肺癌治疗效果开辟新的思路。