Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma.

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. Cancer 2010. © 2010 American Cancer Society.