TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma.
TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma.
复制标题
DOI：
10.1038/srep17622
复制
发表时间：
2015-12-03
影响因子：
4.6
通讯作者：
Hubbell JA
中科院分区：
文献类型：
--
作者：
Damo M;Wilson DS;Simeoni E;Hubbell JA
树突状细胞（DC）衍生的外泌体（Dexo）含有激活有效的抗原特异性免疫应答所必需的机制。作为有前途的无细胞免疫原，Dexo已在先前的癌症疫苗免疫治疗的临床试验中进行了测试，但导致有限的治疗益处。在这里，我们探索了一种新的Dexo疫苗制剂，该制剂由从负载有抗原的DC纯化的Dexo组成，并用TLR-3配体poly（I：C）、TLR-4配体LPS或TLR-9配体CpG-B成熟。当使用poly（I：C）与卵清蛋白（OVA）一起产生外泌体时，所得Dexo疫苗强烈刺激OVA特异性CD 8+和CD 4 + T细胞增殖并获得效应子功能。当B16 F10黑素瘤细胞裂解物用于在外泌体产生期间用肿瘤抗原与poly（I：C）一起加载DC时，我们获得了能够诱导黑素瘤特异性CD 8 + T细胞的稳健活化和细胞毒性CD 8 + T细胞、NK和NK-T细胞募集到肿瘤部位的Dexo疫苗，与类似于先前在人类患者上测试的Dexo疫苗制剂相比，导致肿瘤生长显著减少和存活率提高。我们的研究结果表明，聚（I：C）是一个特别有利的TLR激动剂的DC成熟过程中的抗原加载和外来体生产的癌症免疫治疗。
Dendritic cell (DC)-derived exosomes (Dexo) contain the machinery necessary to activate potent antigen-specific immune responses. As promising cell-free immunogens, Dexo have been tested in previous clinical trials for cancer vaccine immunotherapy, yet resulted in limited therapeutic benefit. Here, we explore a novel Dexo vaccine formulation composed of Dexo purified from DCs loaded with antigens and matured with either the TLR-3 ligand poly(I:C), the TLR-4 ligand LPS or the TLR-9 ligand CpG-B. When poly(I:C) was used to produce exosomes together with ovalbumin (OVA), the resulting Dexo vaccine strongly stimulated OVA-specific CD8+ and CD4+ T cells to proliferate and acquire effector functions. When a B16F10 melanoma cell lysate was used to load DCs with tumor antigens during exosome production together with poly(I:C), we obtained a Dexo vaccine capable of inducing robust activation of melanoma-specific CD8+ T cells and the recruitment of cytotoxic CD8+ T cells, NK and NK-T cells to the tumor site, resulting in significantly reduced tumor growth and enhanced survival as compared to a Dexo vaccine formulation similar to the one previously tested on human patients. Our results indicate that poly(I:C) is a particularly favorable TLR agonist for DC maturation during antigen loading and exosome production for cancer immunotherapy.