Zhang Yue, Wakita Daiko, Chamoto Kenji, Narita Yoshinori, Matsubara Naoki, Kitamura Hidemitsu, Nishimura Takashi
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Int Immunol. 2007 Feb;19(2):151-61. doi: 10.1093/intimm/dxl132. Epub 2006 Dec 22.
We have previously described a method for adoptive immunotherapy of cancer based on antigen-specific T(h)1 cells. However, efficient induction of anti-tumor responses using T(h)1 cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 cells. Tumor-bearing mice were intradermally treated with OVA-specific T(h)1 cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and approximately 50-60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/H-2K(b)-specific CTLs in the tumor DLNs and tumor site. The injected T(h)1 cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic cells. Strikingly, we also found that the accumulation of CD4(+)CD25(+) regulatory T cells (Tregs) was significantly inhibited in tumor DLNs by T(h)1 cell adjuvant therapy and this abrogation was associated with IFNgamma secreted by T(h)1 cells. These results identify T(h)1 cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.
我们之前描述了一种基于抗原特异性辅助性T1（Th1）细胞的癌症过继性免疫疗法。然而，使用Th1细胞有效诱导抗肿瘤反应仍然是一项艰巨的挑战，尤其是对于II类主要组织相容性复合体（MHC）阴性的肿瘤。在本研究中，我们试图开发一种新策略来根除已建立的、表达卵清蛋白（OVA）的II类MHC阴性EG-7细胞肿瘤。荷瘤小鼠在肿瘤引流淋巴结（DLN）附近接受OVA特异性Th1细胞与模型肿瘤抗原（OVA）联合的皮内注射治疗。我们发现该策略可显著抑制肿瘤生长，约50 - 60%的荷瘤小鼠被完全治愈。肿瘤根除关键依赖于肿瘤DLN和肿瘤部位产生OVA/H-2K(b)特异性细胞毒性T淋巴细胞（CTL）。注射的Th1细胞主要分布在肿瘤DLN中，在那里它们大量增殖并增强树突状细胞的活化。引人注目的是，我们还发现Th1细胞辅助治疗可显著抑制肿瘤DLN中CD4(+)CD25(+)调节性T细胞（Treg）的积累，这种消除与Th1细胞分泌的γ干扰素相关。这些结果确定Th1细胞辅助治疗联合肿瘤疫苗接种是一种治疗人类癌症的新方法。
