Thomas Dori A, Massagué Joan
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Cell. 2005 Nov;8(5):369-80. doi: 10.1016/j.ccr.2005.10.012.
Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-beta. However, the mechanism by which TGF-beta inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-beta acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products-namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma-which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-gamma involves binding of TGF-beta-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-beta/Smad pathway. Neutralization of systemic TGF-beta in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-beta suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.
肿瘤通过产生免疫抑制细胞因子转化生长因子-β（TGF-β）来逃避免疫监视。然而，TGF-β在体内抑制T细胞介导的肿瘤清除的机制尚不清楚。我们证明，TGF-β作用于细胞毒性T淋巴细胞（CTL），特异性抑制五种溶细胞基因产物的表达，即穿孔素、颗粒酶A、颗粒酶B、Fas配体和干扰素γ，这些基因产物共同负责CTL介导的肿瘤细胞毒性。颗粒酶B和干扰素-γ的抑制涉及TGF-β激活的Smad和ATF1转录因子与其启动子区域的结合，表明由TGF-β/Smad途径进行直接和选择性调控。在小鼠中中和全身的TGF-β能够实现肿瘤清除，并恢复体内抗原特异性CTL中细胞毒性基因的表达。我们认为，TGF-β通过转录抑制的抗细胞毒性程序在体内抑制CTL功能。
