Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immune-stimulatory modality
Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immune-stimulatory modality
复制标题
坏死性癌细胞-拟态纳米疫苗通过定制的免疫刺激方式增强抗肿瘤免疫力
DOI：
10.1016/j.biomaterials.2018.02.033
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发表时间：
2018-05-01
期刊：
影响因子：
14
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Kang, Ting;Huang, Yukun;Chen, Jun
癌症免疫疗法的最新突破为对抗癌症提供了新的范式转变治疗选择。个性化治疗性抗癌疫苗训练T细胞直接内源性地对抗肿瘤细胞，在与免疫检查点抑制剂协同作用方面提供了巨大的益处。仿生纳米技术提供了一个通用的平台，以提高抗癌免疫力，有效地共同提供优化的免疫原性抗原材料和佐剂的抗原呈递细胞（APC）。坏死性肿瘤细胞可以释放危险相关分子模式（DAMP），如热休克蛋白，比幼稚肿瘤细胞更具免疫原性。在这里，由磷脂双层和磷酸钙核心组成的纳米尺寸的“人工坏死性癌细胞”（α HSP 70 p-CM-CaP）被设计为用于将癌膜蛋白（CM）、DAMP信号增强元件α螺旋HSP 70功能肽（α HSP 70 p）和CpG共同递送至自然杀伤（NK）细胞和APC的柔性疫苗平台。在机械上，免疫原性B16 OVA肿瘤细胞膜相关抗原和α HSP 70 p通过一步水合和封装在磷酸钙核心中的CpG在人工外磷脂双层膜中重构。所得到的α HSP 70 p-CM-CaP具有30 nm的直径，免疫原性膜蛋白保留在颗粒中，以对骨髓来源的树突状细胞的成熟和抗原呈递产生协同作用。在α HSP 70 p-CM-CaP疫苗接种后，在小鼠中观察到有效的淋巴结运输和多表位-T细胞应答。重要的是，α HSP 70 p-CM-CaP还能够诱导表达IFN-γ的CD 8（+）T细胞和NKG 2D（+）NK细胞亚群的扩增。最有希望的是，当在小鼠B160 VA黑素瘤模型上与抗PD-1抗体治疗组合时，α HSP 70 p-CM-CaP疫苗接种导致靶细胞的杀伤和体内肿瘤消退。总之，我们证明了纳米疫苗平台在高效个性化抗癌应用方面的可行性、能力和安全性的概念验证证据。(C)2018爱思唯尔有限公司版权所有
Recent breakthroughs in cancer immunotherapy offer new paradigm-shifting therapeutic options for combating cancer. Personalized therapeutic anti-cancer vaccines training T cells to directly fight against tumor cells endogenously offer tremendous benefits in working synergistically with immune checkpoint inhibitors. Biomimetic nanotechnology offers a versatile platform to boost anticancer immunity by efficiently co-delivering optimized immunogenic antigen materials and adjuvants to antigen presenting cells (APC). Necroptotic tumor cells can release danger associated molecule patterns (DAMPs) like heat shock proteins, being more immunogenic than naive tumor cells. Here, nano-size "artificial necroptotic cancer cell" (alpha HSP70p-CM-CaP) composing of phospholipid bilayer and a phosphate calcium core was designed as a flexible vaccine platform for co-delivering cancer membrane proteins (CM), DAMPs signal augmenting element alpha-helix HSP70 functional peptide (alpha HSP70p) and CpG to both natural killer (NK) cells and APC. Mechanically, immunogenic B16OVA tumor cells membrane-associated antigens and alpha HSP70p were reconstituted in artificial outer phospholipid bilayer membrane via one-step hydration and CpG encapsulated in the phosphate calcium core. The resulted alpha HSP70p-CM-CaP exhibited 30 nm in diameter with the immunogenic membrane proteins reserved in the particles to produce synergistic effect on bone marrow derived dendritic cells maturation and antigen-presentation. Following alpha HSP70p-CM-CaP vaccination, efficient lymph node trafficking and multi-epitope-T cells response was observed in mice. Vitally, alpha HSP70p-CM-CaP was also able to induce expansion of IFN-gamma-expressing CD8(+) T cells and NKG2D(+) NK cells subsets. Most promisingly, alpha HSP70p-CM-CaP vaccination led to the killing of target cells and tumor regression in vivo when combined with anti-PD-1 antibody treatment on mice B16OVA melanoma models. Altogether, we demonstrated proof-of-concept evidence for the feasibility, capability and safety of a nanovaccine platform towards efficient personalized anticancer application. (C) 2018 Elsevier Ltd. All rights reserved.