Cancer · 2010
Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma.
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Chang Wen-Chun, Li Chao-Hsu, Huang Su-Cheng, Chang Daw-Yuan, Chou Li-Yun, Sheu Bor-Ching
Аннотация
BACKGROUND: A study was carried out to determine the functional attributes of CD4(+) CD25(+) regulatory T cells in cancer progression by suppressing antitumor immunity.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.