Nanoenabled Disruption of Multiple Barriers in Antigen Cross-Presentation of Dendritic Cells via Calcium Interference for Enhanced Chemo-Immunotherapy
Nanoenabled Disruption of Multiple Barriers in Antigen Cross-Presentation of Dendritic Cells via Calcium Interference for Enhanced Chemo-Immunotherapy
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DOI：
10.1021/acsnano.0c03881
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发表时间：
2020-06-23
期刊：
影响因子：
17.1
通讯作者：
Shi, Jinjin
中科院分区：
文献类型：
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作者：
An, Jingyi;Zhang, Kaixiang;Shi, Jinjin
化学免疫疗法通过激活T细胞免疫反应，发挥其独特的抗肿瘤作用。然而，肿瘤免疫抑制微环境中树突状细胞(DC)的抗原提呈不足限制了化疗免疫治疗的效果。在这里，我们合理地设计了一种简单而通用的钙离子纳米生成器来破坏树突状细胞内的自噬抑制条件，丰富损伤相关分子模式(DAMP)，并减弱肿瘤微环境中的酸性。化疗后，蜂窝状碳酸钙纳米颗粒(OVA@CaCO3，记为hocn，以卵清蛋白(OVA)为骨架)可优先在肿瘤内蓄积，并显示出一系列的优点：(I)通过hocn诱导的肿瘤酸度降低恢复DC的细胞活力；(Ii)通过在细胞内产生钙离子来破坏DC的自噬抑制状态；(Iii)通过钙超载介导的增强肿瘤细胞释放DAMP来促进DC的成熟。此外，Hocn还可以通过减少免疫抑制细胞和因子的渗透来破坏免疫抑制微环境。我们认为，调节肿瘤内的钙离子为改进癌症的化学免疫治疗提供了一种替代策略。
Chemo-immunotherapy holds the advantage of specific antitumor effects by activating T cell immune response. However, the efficiency of chemo-immunotherapy is restricted to the insufficient antigen presentation of dendritic cells (DCs) in the tumor immunosuppression microenvironment. Here, we rationally designed a simple yet versatile calcium ion nanogenerator to disrupt the autophagy inhibition condition within DCs, enrich damage-associated molecular patterns (DAMPs), and attenuate acidity in the tumor microenvironment. After chemotherapy, honeycomb calcium carbonate (CaCO3) nanoparticles (OVA@CaCO3, denoted as HOCN, ovalbumin (OVA) acted as skeleton) could preferentially accumulate in the tumor and display a series of benefits for disrupting multiple barriers in antigen cross-presentation of DCs: (i) recovering cell viability of DCs by HOCN-induced tumor acidity attenuating; (ii) disrupting the autophagy inhibition condition in DCs by generating Ca2+ in cells; (iii) improving maturation of DCs by Ca2+ overloading-mediated enhanced DAMP release from tumor cells. In addition, HOCN can also disrupt the immunosuppressive microenvironment by reducing the infiltration of immunosuppressive cells and factors. We believe regulation of the intratumoral Ca2+ offers an alternative strategy for improving cancer chemo-immunotherapy.