Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
Cancer. 2010 Dec 15;116(24):5777-88. doi: 10.1002/cncr.25371. Epub 2010 Aug 23.
A study was carried out to determine the functional attributes of CD4(+) CD25(+) regulatory T cells in cancer progression by suppressing antitumor immunity.
Triple-color flow cytometry was used to study the phenotype expression of CD4(+) CD25(+) regulatory T cells and CD8(+) T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters.
The prevalence of CD4(+) CD25(+) T cells was significantly higher in the TILs than PBLs. The expression of CD4(+) CD25(+) regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4(+) CD25(+) regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8(+) T cells were CD28(-) CD45RA(-) CD45RO(+) CCR7(-) , suggesting good terminal differentiation. Most of them had an activated role with CD69(+) CD103(+) CD152(+) . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8(+) cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8(+) cytotoxic T cells.
Regulatory T cells in the tumor microenvironment may abrogate CD8(+) T cell cytotoxicity in a granzyme B- and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression.
本研究旨在通过抑制抗肿瘤免疫来确定 CD4(+) CD25(+)调节性 T 细胞在癌症进展中的功能属性。
采用三色流式细胞术研究 57 例Ⅰ期至Ⅳ期子宫内膜癌患者外周血淋巴细胞（PBLs）和肿瘤浸润淋巴细胞（TILs）中 CD4(+) CD25(+)调节性 T 细胞和 CD8(+) T 细胞的表型表达。T 细胞亚群的表达与临床预后参数相关。
TILs 中 CD4(+) CD25(+) T 细胞的比例明显高于 PBLs。肿瘤微环境中 CD4(+) CD25(+)调节性 T 细胞的表达与肿瘤分级、分期和肌层浸润有关。PBLs 中 CD4(+) CD25(+)调节性 T 细胞中 FOXP3 和 GITR 的表达低于 TILs。大多数浸润肿瘤的 CD8(+) T 细胞呈 CD28(-) CD45RA(-) CD45RO(+) CCR7(-) ，提示其终末分化良好。它们大多具有激活作用，表达 CD69(+) CD103(+) CD152(+) 。功能上，外周调节性 T 细胞中几乎不表达 granzyme B 和 perforin，但在肿瘤微环境中的外周调节性 T 细胞中高表达。相比之下，源自 PBL 的 CD8(+)细胞毒性 T 细胞表达 granzyme B 和 perforin，且表达水平显著高于 TIL。进一步的功能测定表明，Th1 细胞因子和细胞毒性分子可在外周 CD8(+)细胞毒性 T 细胞中同步上调。
肿瘤微环境中的调节性 T 细胞可能通过 granzyme B 和 perforin 依赖的途径消除 CD8(+) T 细胞的细胞毒性。Th1 细胞因子和细胞毒性酶的减少与调节性 T 细胞介导的体内肿瘤清除受限有关。具有临床意义的是，TIL 中调节性 T 细胞的表达可能在肿瘤微环境中介导 T 细胞免疫抑制，因此与癌症进展密切相关。
