Cholesterol-modified DP7 enhances the effect of individualized cancer immunotherapy based on neoantigens.
Cholesterol-modified DP7 enhances the effect of individualized cancer immunotherapy based on neoantigens.
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DOI：
10.1016/j.biomaterials.2020.119852
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发表时间：
2020-02
期刊：
影响因子：
14
通讯作者：
Rui Zhang;Lin Tang;Yaomei Tian;X. Ji;Qiuyue Hu;Bailing Zhou;Z. Ding;Xueli Heng;Li Yang
中科院分区：
文献类型：
--
作者：
Rui Zhang;Lin Tang;Yaomei Tian;X. Ji;Qiuyue Hu;Bailing Zhou;Z. Ding;Xueli Heng;Li Yang
基于新抗原的个体化肿瘤疫苗已成为肿瘤免疫治疗的重要研究方向。然而，它们的治疗效果受到抗原摄取和抗原呈递细胞呈递的效率的限制。在这里，具有载体和免疫佐剂双重功能的低毒性胆固醇修饰抗菌肽（AMP） DP7 （DP7- c）提高了基于树突状细胞（DC）的疫苗效力。作为递送载体，DP7-C可以通过小洞蛋白和网格蛋白依赖途径将各种抗原肽有效地递送到75-95%的dc中。DP7-C作为免疫佐剂，可通过TLR2-MyD88-NF-κB通路诱导DC成熟和促炎细胞因子释放，有效提高抗原提呈效率。此外，DP7-C增强了基于dc的个体化癌症免疫治疗的疗效，并在使用OVA抗原肽和LL2-neoantigens的小鼠肿瘤模型上取得了优异的抗肿瘤效果。令人兴奋的是，在DP7-C刺激后，晚期肺癌患者单核细胞源性dc （MoDCs）的抗原摄取效率从14-40%增加到88-98%，呈现效率从约15%增加到约65%，成熟MoDCs的比例从约20%增加到约60%。这些发现表明，我们的方法可能是为个体患者生产癌症疫苗的潜在替代策略。
Personalized cancer vaccines based on neoantigens have become an important research direction in cancer immunotherapy. However, their therapeutic effects are limited by the efficiency of antigen uptake and presentation by antigen presenting cells. Here, the low-toxicity cholesterol-modified antimicrobial peptide (AMP) DP7 (DP7-C), which has dual functions as a carrier and an immune adjuvant, improved the dendritic cell (DC)-based vaccine efficacy. As a delivery carrier, DP7-C can efficiently delivery various antigen peptides into 75–95% of DCs via caveolin- and clathrin-dependent pathways. As an immune adjuvant, DP7-C can induce DC maturation and proinflammatory cytokine release via the TLR2-MyD88-NF-κB pathway and effectively increase antigen presentation efficiency. In addition, DP7-C enhanced the efficacy of DC-based individualized cancer immunotherapy and achieved excellent antitumor effects on mouse tumor models using the OVA antigen peptides and LL2-neoantigens. Excitingly, after DP7-C stimulation, the antigen uptake efficiency of monocytes-derived DCs (MoDCs) in patients with advanced lung cancer increased from 14-40% to 88–98%, the presentation efficiency increased from approximately 15% to approximately 65%, and the proportion of mature MoDCs increased from approximately 20% to approximately 60%. These findings suggest that our approach may be a potentially alternative strategy to produce cancer vaccines designed for individual patients.