Inhibition of Transforming Growth Factor-β-Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types
Inhibition of Transforming Growth Factor-β-Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types
复制标题
DOI：
10.1158/0008-5472.can-08-2499
复制
发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Ogasawara, Kazumasa
中科院分区：
文献类型：
--
作者：
Fujita, Takuya;Teramoto, Koji;Ogasawara, Kazumasa
肿瘤引流淋巴结（DLN）是产生抗肿瘤免疫应答的最重要的引发部位。它们也是免疫抑制细胞因子转化生长因子-β（TGF-β）在抑制这些抗肿瘤免疫应答中起关键作用的位置。我们专注于TGF-β介导的免疫抑制DLN和检查是否局部抑制TGF-β增强抗肿瘤免疫反应的荷瘤小鼠模型全身。为了抑制DLN中TGF-β介导的免疫抑制，皮下携带E.G7肿瘤的C57 BL/6小鼠经肌肉注射施用编码融合于人IgG重链的TGF-β II型受体的胞外结构域（TGFR DNA）的质粒DNA。在肿瘤附近在DLN中，TGF-β的抑制抑制了调节性T细胞的增殖，并增加了产生IFN-γ的肿瘤抗原特异性CD 4（+）或CD 8（+）细胞的数量。DLN中抗肿瘤免疫应答的增强与脾脏中肿瘤抗原特异性细胞毒性和自然杀伤活性的增强以及血清中肿瘤特异性抗体水平的升高相关。通过增强的抗肿瘤免疫应答，有效抑制了已建立的转移性肿瘤和原发性肿瘤的生长。DLN中TGF-β介导的免疫抑制的抑制与各种免疫活性细胞类型增强的抗肿瘤反应显着相关。该动物模型为靶向TGF-β的分子癌症治疗提供了新的理论基础。[Cancer Res 2009;69（12）：5142-50]
Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-beta-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-beta augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-beta-mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model pro-vides a novel rationale for molecular cancer therapeutics targeting TGF-beta. [Cancer Res 2009;69(12):5142-50]