Department of Immunology, Laboratory of Dendritic Cell Differentiation and Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea;
Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea;
J Immunol. 2014 Aug 1;193(3):1233-45. doi: 10.4049/jimmunol.1400656. Epub 2014 Jul 2.
Despite the potential for stimulation of robust antitumor immunity by dendritic cells (DCs), clinical applications of DC-based immunotherapy are limited by the low potency in generating tumor Ag-specific T cell responses. Therefore, optimal conditions for generating potent immunostimulatory DCs that overcome tolerance and suppression are key factors in DC-based tumor immunotherapy. In this study, we demonstrate that use of the Mycobacterium tuberculosis heat shock protein X (HspX) as an immunoadjuvant in DC-based tumor immunotherapy has significant potential in therapeutics. In particular, the treatment aids the induction of tumor-reactive T cell responses, especially tumor-specific CTLs. The HspX protein induces DC maturation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6, and IFN-β) through TLR4 binding partially mediated by both the MyD88 and the TRIF signaling pathways. We employed two models of tumor progression and metastasis to evaluate HspX-stimulated DCs in vivo. The administration of HspX-stimulated DCs increased the activation of naive T cells, effectively polarizing the CD4(+) and CD8(+) T cells to secrete IFN-γ, as well as enhanced the cytotoxicity of splenocytes against HPV-16 E7 (E7)-expressing TC-1 murine tumor cells in therapeutic experimental animals. Moreover, the metastatic capacity of B16-BL6 melanoma cancer cells toward the lungs was remarkably attenuated in mice that received HspX-stimulated DCs. In conclusion, the high therapeutic response rates with tumor-targeted Th1-type T cell immunity as a result of HspX-stimulated DCs in two models suggest that HspX harnesses the exquisite immunological power and specificity of DCs for the treatment of tumors.
尽管树突状细胞（DC）具有刺激抗肿瘤免疫的潜力，但基于 DC 的免疫疗法的临床应用受到产生肿瘤 Ag 特异性 T 细胞反应的低效力的限制。因此，产生克服耐受和抑制的有效免疫刺激性 DC 的最佳条件是基于 DC 的肿瘤免疫治疗的关键因素。在这项研究中，我们证明了结核分枝杆菌热休克蛋白 X（HspX）作为基于 DC 的肿瘤免疫治疗中的免疫佐剂的使用在治疗学上具有显著的潜力。特别是，该治疗方法有助于诱导肿瘤反应性 T 细胞反应，特别是肿瘤特异性 CTL。HspX 蛋白通过 TLR4 结合诱导 DC 成熟和促炎细胞因子的产生（TNF-α、IL-1β、IL-6 和 IFN-β），该结合部分由 MyD88 和 TRIF 信号通路介导。我们采用了两种肿瘤进展和转移模型来评估体内 HspX 刺激的 DC。HspX 刺激的 DC 的给药增加了幼稚 T 细胞的激活，有效地将 CD4（+）和 CD8（+）T 细胞极化以分泌 IFN-γ，并增强了针对 HPV-16 E7（E7）表达的 TC-1 小鼠肿瘤细胞的脾细胞的细胞毒性在治疗实验动物中。此外，接受 HspX 刺激的 DC 的 B16-BL6 黑色素瘤癌细胞向肺部的转移能力显著减弱。总之，由于两种模型中的 HspX 刺激的 DC 导致针对肿瘤的靶向 Th1 型 T 细胞免疫，因此具有高治疗反应率，这表明 HspX 利用了 DC 的精密免疫力量和特异性来治疗肿瘤。
