Moo-Young Tricia A, Larson Justin W, Belt Brian A, Tan Marcus C, Hawkins William G, Eberlein Timothy J, Goedegebuure Peter S, Linehan David C
Laboratory for Biologic Cancer Therapy, Department of Surgery, Washington University School of Medicine, Saint Louis, MO 63110, USA.
J Immunother. 2009 Jan;32(1):12-21. doi: 10.1097/CJI.0b013e318189f13c.
CD4+25+Foxp3+ regulatory T cells (Treg) play a critical role in the induction of tolerance to tumor-associated antigens and suppression of antitumor immunity. How Treg are induced in cancer is poorly understood. We reported previously that Treg are significantly elevated in the peripheral blood of patients with pancreas cancer and that in a murine pancreas cancer model induction of Treg seems to be transforming growth factor (TGF)-beta dependent. Here we provide additional evidence that Treg are increased locally within the tumor microenvironment by a mechanism that seems dependent on TGF-beta receptor expression and the presence of tumor derived TGF-beta. The murine pancreas cancer cell line Pan02 produces high levels of TGF-beta both in vitro and in vivo. In contrast, the esophageal murine cancer cell line, Eso2, does not. Immunohistochemical staining of Foxp3 in explanted tumors shows an identifiable population of Treg in the Pan02 (TGF-beta positive) tumors but not Eso2 (TGF-beta negative). Naive CD4+25-Foxp3- T cells, when adoptively transferred into Rag-/- mice, are converted into Foxp3+ Treg in the presence of Pan02 but not Eso2 tumors. Induction of Treg in Pan02 mice is blocked by systemic injection of an anti-TGF-beta antibody. If Rag-/- mice are instead reconstituted with naive CD4+25- T cells expressing a mutated TGF-beta receptor, induction of Foxp3+ Treg in Pan02 bearing mice is blocked. Collectively, these observations further support the role of TGF-beta in the induction of Treg in pancreas adenocarcinoma.
CD4+25+Foxp3+调节性T细胞（Treg）在诱导对肿瘤相关抗原的耐受性和抑制抗肿瘤免疫中发挥着关键作用。目前对癌症中Treg的诱导机制了解甚少。我们之前报道过，胰腺癌患者外周血中的Treg显著升高，并且在小鼠胰腺癌模型中，Treg的诱导似乎依赖于转化生长因子（TGF）-β。在此，我们提供了额外的证据，表明Treg通过一种似乎依赖于TGF-β受体表达和肿瘤来源TGF-β存在的机制在肿瘤微环境中局部增加。小鼠胰腺癌细胞系Pan02在体外和体内均产生高水平的TGF-β。相比之下，食管小鼠癌细胞系Eso2则不产生。对移植瘤进行Foxp3免疫组化染色显示，在Pan02（TGF-β阳性）肿瘤中有可识别的Treg群体，而在Eso2（TGF-β阴性）肿瘤中则没有。当将初始CD4+25-Foxp3-T细胞过继转移到Rag-/-小鼠体内时，在存在Pan02肿瘤而非Eso2肿瘤的情况下，这些细胞会转化为Foxp3+Treg。Pan02小鼠中Treg的诱导可被全身注射抗TGF-β抗体阻断。如果用表达突变型TGF-β受体的初始CD4+25-T细胞重建Rag-/-小鼠，则携带Pan02肿瘤的小鼠中Foxp3+Treg的诱导会被阻断。总体而言，这些观察结果进一步支持了TGF-β在胰腺腺癌中Treg诱导过程中的作用。
