Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy
Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy
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利用基于纳米载体的药物递送系统诱导增强的免疫原性细胞死亡用于胰腺癌治疗
DOI：
10.1016/j.biomaterials.2016.06.032
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发表时间：
2016
期刊：
影响因子：
14
通讯作者：
Nie Guangjun
中科院分区：
文献类型：
--
作者：
Zhao Xiao;Yang Keni;Zhao Ruifang;Ji Tianjiao;Wang Xiuchao;Yang Xiao;Zhang Yinlong;Cheng Keman;Liu Shaoli;Hao Jihui;Ren He;Leong Kam W.;Nie Guangjun
免疫原性细胞死亡（ICD）是指凋亡的肿瘤细胞通过释放免疫刺激性损伤相关分子模式（DAMP），激发特异性免疫应答，从而发挥抗肿瘤作用。假设纳米药物可能会影响ICD，因为它们在递送化疗药物方面的优势已经得到证实，我们将奥沙利铂（OXA）或吉西他滨（GEM）（分别为ICD和非ICD诱导剂）封装到两亲性二嵌段共聚物纳米颗粒中。GEM和纳米粒包封的GEM（NP-GEM）均不诱导ICD，而OXA和纳米粒包封的OXA（NP-OXA）均诱导ICD。有趣的是，NP-OXA处理的肿瘤细胞比OXA处理的肿瘤细胞释放更多的DAMP，并诱导树突状细胞和T淋巴细胞的更强的免疫应答。此外，OXA和NP-OXA在免疫活性小鼠中比在免疫缺陷小鼠中表现出更强的治疗效果，并且在NP-OXA组中治疗效果的增强显著高于OXA组。此外，NP-OXA处理比OXA处理诱导更高比例的肿瘤浸润活化的细胞毒性T淋巴细胞。在评价另一对ICD诱导剂和非ICD诱导剂多柔比星和5-氟尿嘧啶时，证实了通过纳米颗粒递送增强ICD的这种总体趋势。总之，尽管纳米颗粒包封没有赋予非ICD诱导剂ICD介导的抗肿瘤能力，但用纳米颗粒包封的ICD诱导剂治疗导致显著增强的ICD，从而比游离ICD诱导剂改善抗肿瘤作用。提出的纳米医学方法可能会通过ICD的新细胞死亡机制影响癌症免疫治疗。
Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatmentin vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD.