A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy
A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy
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DOI：
10.1172/jci44327
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Spencer, David M.
中科院分区：
文献类型：
--
作者：
Narayanan, Priyadharshini;Lapteva, Natalia;Spencer, David M.
基于DC的癌症疫苗的体内治疗功效受到次优DC成熟方案的限制。尽管TLR佐剂的递送全身性地增强了基于DC的癌症疫苗的功效，但它也可能增加毒性。在此，我们已经工程化了用于DC的药物诱导型复合活化受体（在本文中称为DC-CAR），其包含TLR衔接子MyD 88、CD 40胞质区和2个配体结合FKBP 12结构域。给药脂质渗透二聚化配体（AP 1903）诱导寡聚化和激活这种融合蛋白，我们称之为iMyD 88/CD 40。向接种疫苗的小鼠施用AP 1903能够延长iMyD 88/CD 40修饰的DC的靶向活化。与常规成熟DC相比，AP 1903激活的iMyD 88/CD 40-DC具有增加的促炎性MAPK活化。AP 1903激活的iMyD 88/CD 40转导的人或小鼠DC也产生更高水平的Th 1细胞因子，显示出改善的体内迁移，并增强抗原特异性CD 8（+）T细胞应答和先天性NK细胞应答。此外，在接种疫苗的小鼠中用AP 1903处理导致针对预先建立的E.G7-OVA淋巴瘤和侵袭性B16.F10肿瘤的稳健的抗肿瘤免疫。因此，iMyD 88/CD 40统一的“开关”有效且安全地替代外源性佐剂混合物，允许体内远程且持续的DC活化。通过iMyD 88/CD 40的DC“许可”可能代表了一种机制，通过该机制使用单个小分子药物来利用DC中TLR和CD 40信号传导途径之间的天然协同作用，并且可以增强基于抗肿瘤DC的疫苗的功效。
The in vivo therapeutic efficacy of DC-based cancer vaccines is limited by suboptimal DC maturation protocols. Although delivery of TLR adjuvants systemically boosts DC-based cancer vaccine efficacy, it could also increase toxicity. Here, we have engineered a drug-inducible, composite activation receptor for DCs (referred to herein as DC-CAR) comprising the TLR adaptor MyD88, the CD40 cytoplasmic region, and 2 ligand-binding FKBP12 domains. Administration of a lipid-permeant dimerizing ligand (AP1903) induced oligomerization and activation of this fusion protein, which we termed iMyD88/CD40. AP1903 administration to vaccinated mice enabled prolonged and targeted activation of iMyD88/CD40-modified DCs. Compared with conventionally matured DCs, AP1903-activated iMyD88/CD40-DCs had increased activation of proinflammatory MAPKs. AP1903-activated iMyD88/CD40-transduced human or mouse DCs also produced higher levels of Th1 cytokines, showed improved migration in vivo, and enhanced both antigen-specific CD8(+) T cell responses and innate NK cell responses. Furthermore, treatment with AP1903 in vaccinated mice led to robust antitumor immunity against preestablished E.G7-OVA lymphomas and aggressive B16.F10 tumors. Thus, the iMyD88/CD40 unified "switch" effectively and safely replaced exogenous adjuvant cocktails, allowing remote and sustained DC activation in vivo. DC "licensing" through iMyD88/CD40 may represent a mechanism by which to exploit the natural synergy between the TLR and CD40 signaling pathways in DCs using a single small molecule drug and could augment the efficacy of antitumor DC-based vaccines.