Enhanced Efficacy of Therapeutic Cancer Vaccines Produced by Co-Treatment with Mycobacterium tuberculosis Heparin-Binding Hemagglutinin, a Novel TLR4 Agonist
Enhanced Efficacy of Therapeutic Cancer Vaccines Produced by Co-Treatment with Mycobacterium tuberculosis Heparin-Binding Hemagglutinin, a Novel TLR4 Agonist
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DOI：
10.1158/0008-5472.can-10-3487
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Park, Yeong-Min
中科院分区：
文献类型：
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作者：
Jung, In Duk;Jeong, Soo Kyung;Park, Yeong-Min
有效激活树突状细胞（DCs）向辅助性T细胞（Th）-1极化将改善基于DC的抗肿瘤免疫治疗，有助于促进基于T细胞免疫的免疫疫苗的开发。为了实现这一目标，必须开发有效的免疫佐剂，可以诱导强大的Th 1细胞免疫应答。病原生物结核分枝杆菌包括某些成分，如肝素结合血凝素（HBHA），具有很强的免疫刺激潜力。在这项研究中，我们首次阐明了HBHA在与癌症相关的免疫刺激环境中的功能和确切机制。HBHA以TLR 4依赖性方式诱导DC成熟，提高表面分子CD 40、CD 80和CD 86、MHC I类和II类以及促炎细胞因子IL-6、IL-12、IL-1 β、TNF-α和CCR 7的表达，以及刺激体外和体内DC的迁移能力。机制研究证实，TLR 4下游的MyD 88和TRIF信号通路介导HBHA诱导的促炎细胞因子的分泌。HBHA处理的DC激活初始T细胞，极化CD 4（+）和CD 8（+）T细胞以分泌IFN-γ，并诱导T细胞介导的细胞毒性。值得注意的是，经HBHA处理和OVA（251-264）离体脉冲的DC的全身施用大大增强了体内免疫引发，诱导了与鼠E.G7胸腺瘤模型中的长期存活相关的肿瘤生长的显著消退。总之，我们的研究结果突出了HBHA作为一种免疫佐剂，有利于Th 1极化和DC功能的DC为基础的抗肿瘤免疫治疗的潜在应用。Cancer Res; 71（8）; 2858-70.（C）2011年《非洲标准化评论》。
Effective activation of dendritic cells (DCs) toward T helper (Th)-1 cell polarization would improve DC-based antitumor immunotherapy, helping promote the development of immunotherapeutic vaccines based on T-cell immunity. To achieve this goal, it is essential to develop effective immune adjuvants that can induce powerful Th1 cell immune responses. The pathogenic organism Mycobacterium tuberculosis includes certain constitutes, such as heparin-binding hemagglutinin (HBHA), that possess a strong immunostimulatory potential. In this study, we report the first clarification of the functions and precise mechanism of HBHA in immune stimulation settings relevant to cancer. HBHA induced DC maturation in a TLR4-dependent manner, elevating expression of the surface molecules CD40, CD80, and CD86, MHC classes I and II and the proinflammatory cytokines IL-6, IL-12, IL-1 beta, TNF-alpha, and CCR7, as well as stimulating the migratory capacity of DCs in vitro and in vivo. Mechanistic investigations established that MyD88 and TRIF signaling pathways downstream of TLR4 mediated secretion of HBHA-induced proinflammatory cytokines. HBHA-treated DCs activated naive T cells, polarized CD4(+) and CD8(+) T cells to secrete IFN-gamma, and induced T-cell-mediated cytotoxicity. Notably, systemic administration of DCs that were HBHA-treated and OVA(251-264)-pulsed ex vivo greatly strengthened immune priming in vivo, inducing a dramatic regression of tumor growth associated with long-term survival in a murine E.G7 thymoma model. Together, our findings highlight HBHA as an immune adjuvant that favors Th1 polarization and DC function for potential applications in DC-based antitumor immunotherapy. Cancer Res; 71(8); 2858-70. (C)2011 AACR.