负载化疗药物的肿瘤微颗粒：重塑肺癌癌性胸水免疫微环境的机理探究

It is lack of effective treatment to cure end-stage lung cancer with metastatic malignant pleural effusion. However, tumor cell-derived chemotherapeutic microparticles showed a significant therapeutic effects. Our previous study showed the drug loaded microparticles could not only induce the death of tumor cells, but also induce the polarization of macrophages from M2 to M1 type. The further study showed that N1 type neutrophils which cytotoxic to tumor cells were abundant recruitment from the blood vessels to the chest after drug loaded microparticles were intrapleural injection, suggesting that the drug loaded microparticles in addition to kill the tumor cells directly, but also may affect the immune cells of pleural effusion, mediating the secondary killing to tumor cells. Based on this, we intend to explore the changes and mechanisms of various immune cell subsets in lung tumor microenvironment. This project will answer the immunological mechanism of drug loaded microparticles in the effective treatment of pleural effusion and provide new strategies and ideas for the new tumor immunotherapy.

肺部肿瘤的形成与肺部的组织结构和局部免疫微环境密切相关。随着肺癌细胞的不断生长，其往往会侵犯胸腔形成癌性胸水。胸腔内免疫抑制细胞群体营造了促肿瘤生长微环境，进一步导致恶性胸水积聚，目前针对中晚期肺癌并发的癌性胸水尚缺乏有效治疗手段。负载化疗药物的肿瘤微颗粒对癌性胸水，已显示出良好的治疗效果。申请人前期研究表明，载药微颗粒不但有效诱导肿瘤细胞死亡，而且其被巨噬细胞摄取后，可诱导巨噬细胞由M2型向M1型转化。进一步研究发现，经载药微颗粒治疗后，胸水中抗肿瘤的N1型中性粒细胞显著增加，提示载药微颗粒除了直接杀伤肿瘤细胞外，还可能通过影响胸水中的免疫细胞，介导对肿瘤细胞的二次杀灭。基于此，本项目拟深入探究经载药微颗粒治疗后肺部微环境中各类免疫细胞亚群的变化及其机理。本课题的完成，有望推动载药微颗粒这一集生物化疗与免疫治疗为一体的肿瘤复合疗法，为新型肿瘤免疫生物治疗提供新策略和新思路。

恶性胸腔积液常见于肿瘤晚期且治疗效果不佳。因此，急需寻找新的有效的恶性胸腔积液的治疗方式。申请人课题组前期研究表明，微颗粒作为载体递送化疗药对肿瘤具有治疗杀伤作用，并有效的杀伤肿瘤再生细胞。申请人进一步研究发现，胸腔灌注载药微颗粒后，首先，肿瘤细胞摄取载药微颗粒并被杀死；其次巨噬细胞摄取载药微颗粒，并释放趋化因子CXCL1和CXCL2招募中性粒细胞至胸腔杀伤肿瘤细胞；再次载药微颗粒灌注后，改变胸腔微环境，中性粒细胞被活化，活化的中性粒细胞对肿瘤细胞发起第二波杀伤；最后，中性粒细胞释放NET，覆盖血管内皮细胞缝隙，降低内皮细胞的通透性进而消退胸腔积液。这些研究从全新的角度阐述中性粒细胞杀伤肿瘤，尤其是控制恶性胸腔积液，为肿瘤免疫治疗提供新的手段和方法。