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Published on: January 3, 2013
B7-H4 overexpression impairs the immune response of T cells in human cervical carcinomas
Xin Wang1, Tingting Wang1, Man Xu1
1Department of Pathology, Molecular Medicine and Tumor Research Center of Chongqing Medical University, Chongqing, China.
Objective:
To investigate B7-H4 expression and its correlation with the number of infiltrating T lymphocytes and cytokine production by those lymphocytes in human cervical cancer and to determine the effect of recombinant B7-H4 on the active peripheral blood T cells of the patients in vitro.
Methods:
B7-H4 expression was detected in 67 cases of cervical cancer using immunohistochemical staining. Tumor-infiltrating CD8(+)T, CD4(+)T, and FOXP3(+) (Forkhead Box P3) T lymphocytes and their levels of IFN-γ and TGF-β₁ production were determined by immunofluorescent double-staining. After the peripheral blood T lymphocytes of patients were co-cultured with B7-H4, proliferation, apoptosis, and cell subtypes were analyzed using flow cytometry. Cytokines in the supernatant were detected by ELISA.
Results:
B7-H4 was expressed in 46% (31/67) of the cases of cervical cancer. The number of infiltrating CD8(+)T lymphocytes and their IFN-γ production in positive B7-H4 expression cervical cancers was significantly lower than in negative B7-H4 cases (P<0.01, P<0.05), but there was no significant difference between cases positive and negative for B7-H4 with respect to infiltrating FOXP3(+)T and CD4(+)T cells or TGF-β1 production. After co-culture with B7-H4 for 48 h, the patients' activated T lymphocytes were arrested at G1/G2 phase. The Ki67 positive rates of CD4(+)T and CD8(+)T cells were 2.13 ± 0.13% and 1.03 ± 1.33%, and they were lower than in the blank group. The proportion of CD4(+)T and CD8(+)T cells decreased, but CD4(+)T/CD8(+)T and the proportion of CD4(+)CD25(+)Foxp3(+)T cells increased. In addition, concentrations of IL-10 and TGF-β1 in the supernatant of co-cultured T cells increased significantly (P<0.05, P<0.05), but that of IFN-γ decreased. B7-H4 had no significant effect on apoptosis of the T cells.
Conclusion:
B7-H4 is overexpressed in human cervical cancers, and it is associated with lower numbers of tumor-infiltrating CD8(+)T lymphocytes and therefore less IFN-γ production. In vitro, B7-H4 inhibits the proliferation of CD4(+)T and CD8(+)T but promotes the proliferation of Tregs and the secretion of IL-10 and TGF-β1. B7-H4 plays an important role in depressing the anti-tumor immunity of CD8(+)T cell in microenvironments of cervical cancer.
