Department of Veterinary Pathology, Nippon Veterinary and Life-science University (NVLU), Tokyo, Japan.
Eur J Immunol. 2010 Apr;40(4):1011-21. doi: 10.1002/eji.200939513.
Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.
癌症诱导的免疫耐受由诱导性 Treg（iTreg）介导，是癌症免疫治疗的主要障碍。在免疫耐受的基础研究中，将内源性超抗原，即次要淋巴细胞刺激（Mls）-1(a)，注射到特异性 TCR Vbeta8.1-Tg 小鼠中，可产生无能的 CD25(-)iTreg，其免疫抑制功能通过 p38-MAPK 激活来维持 IL-10 的产生。有趣的是，尽管 p38-化学抑制剂（p38-inhibitor）能够打破 CD25(-)iTreg 诱导的免疫耐受，但当存在 CD25(+)Treg 时，p38-inhibitor 几乎没有免疫耐受破坏作用，这表明 CD25(+)Treg 的耗竭对于 p38-inhibitor 的有效性是必要的。肽 OVA(323-339)iv.-注射到其特异性 TCR-Tg (OT-II) 小鼠中也通过 iTreg 诱导适应性耐受。在通过过继转移 OT-II CD25(-)iTreg 建立的表达 OVA 的淋巴瘤 E.G7 耐受模型中，在 CD25(+)Treg 耗竭后进行 p38-inhibitor 肽免疫治疗，导致肿瘤生长受到抑制。同样，在结肠癌 CT26 荷瘤小鼠中，由于 IL-10 分泌 iTreg 的数量增加，肽免疫治疗诱导的抗肿瘤免疫增强，通过 CD25(+)Treg 耗竭后使用 p38-inhibitor 治疗可抑制肿瘤进展。这些结果表明，同时抑制两种不同的 Treg 功能可能对癌症免疫治疗的成功至关重要。
