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

• Published in: Cancer 2010-12, Vol.116 (24), p.5777-5788
• Main Authors: Chang, Wen‐Chun, Li, Chao‐Hsu, Huang, Su‐Cheng, Chang, Daw‐Yuan, Chou, Li‐Yun, Sheu, Bor‐Ching
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Disease Progression; endometrial carcinoma; Endometrial Neoplasms - immunology; Female; Female genital diseases; granzyme B; Gynecology. Andrology. Obstetrics; Humans; Immune Tolerance; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; perforin; regulatory T cells; T-Lymphocytes, Regulatory - immunology; Tumors; tumor‐infiltrating lymphocytes
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.25371

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. Regulatory T cells in the tumor microenvironment may abrogate CD8+ T cell cytotoxicity in a granzyme B‐ and perforin‐dependent conduit. Of clinical significance, the expression of regulatory T cells in tumor‐infiltrating lymphocytes may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression.