Smart Nanovesicle-Mediated Immunogenic Cell Death through Tumor Microenvironment Modulation for Effective Photodynamic Immunotherapy
Smart Nanovesicle-Mediated Immunogenic Cell Death through Tumor Microenvironment Modulation for Effective Photodynamic Immunotherapy
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通过肿瘤微环境调节智能纳米囊泡介导的免疫原性细胞死亡，实现有效的光动力免疫治疗
DOI：
10.1021/acsnano.9b07212
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发表时间：
2020-01-01
期刊：
影响因子：
17.1
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Yang, Weijing;Zhang, Fuwu;Chen, Xiaoyuan
联合治疗可以更好地平衡免疫激活和抑制信号，在癌症免疫治疗中具有巨大的潜力。在这里，我们偶然发现，由嵌段共聚聚乙二醇b-阳离子多肽自组装的pH响应型纳米微囊(PRNV)不仅可以作为纳米载体，而且可以通过钙网蛋白的预凋亡暴露而导致免疫原性细胞死亡(ICD)。在B16F10黑色素瘤模型中，光敏剂2-(1-己氧乙基)-2-去乙烯焦脱镁叶绿酸-a(HPPH)和吲哚-2，3-双加氧酶抑制剂吲哚肟(Ind)共包裹后，pRNvs/HPPH/Ind在单次低剂量激光照射后可产生显著的抗肿瘤效果和异常效应。治疗效果归因于三个关键因素：(1)HPPH介导的光动力疗法(PDT)产生单线态氧；(2)增加pRNvs和PDT诱导的ICD后树突状细胞(DC)募集和免疫反应；(3)IND通过促进CD8(+)T细胞的P-S6K磷酸化来调节肿瘤微环境。本研究利用纳米载体诱导ICD以激活宿主的免疫功能。这种一体式智能纳米胶囊可以设计多功能材料，以增强癌症免疫治疗的疗效。
Combination therapy that could better balance immune activation and suppressive signals holds great potential in cancer immunotherapy. Herein, we serendipitously found that the pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol-b-cationic polypeptide can not only serve as a nanocarrier but also cause immunogenic cell death (ICD) through preapoptotic exposure of calreticulin. After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model. Treatment efficacy attributes to three key factors: (i) singlet oxygen generation by HPPH-mediated photodynamic therapy (PDT); (ii) increased dendritic cell (DC) recruitment and immune response provocation after ICD induced by pRNVs and PDT; and (iii) tumor microenvironment modulation by IND via enhancing P-S6K phosphorylation for CD8(+) T cell development. This study exploited the nanocarrier to induce ICD for the host's immunity activation. The "all-in-one" smart nanovesicles allow the design of multifunctional materials to strengthen cancer immunotherapy efficacy.