Aberrant expression of B7-H4 correlates with poor prognosis and suppresses tumor-infiltration of CD8+ T lymphocytes in human cholangiocarcinoma

Abstract

B7-H4, as a member of the costimulatory B7 family, serves a critical role in the negative regulation of T cell-mediated antitumor immune responses. Cholangiocarcinoma (CCA) has a poor prognosis due its invasiveness and associated metastasis. The present study investigated the expression of B7-H4 in patients with CCA and its association with patient prognosis. The correlation between B7-H4 expression and CD4+ and CD8+ tumor-infiltrating lymphocytes was also investigated. The results demonstrated that high B7-H4 expression was detected in cancer tissues (54/110; 49.1%) compared with that noted in chronic inflammatory bile duct tissues (4/19; 21.1%). Furthermore, all 8 biliary adenoma samples showed negative staining. The expression of B7-H4 was significantly associated with adverse clinical and pathological features including histologic grade (P<0.001), tumor status (P=0.025), lymph node metastasis (P=0.035) and 6th Union for International Cancer Control stage (P=0.019). Kaplan‑Meier survival analysis and Cox regression analysis indicated that aberrant B7-H4 expression was a significant independent predictor of poor overall survival and early recurrence. In addition, the present study demonstrated that B7-H4 expression in tumor cells was negatively correlated with the density of CD8+ T cells in the tumor stroma. Co-culture assays indicated that knockdown of B7-H4 increased CD8+ T cell-mediated cytotoxicity in vitro, suggesting that the expression of B7-H4 may serve a role in shielding tumors from immune surveillance by suppression of tumor-infiltrating CD8+ T lymphocytes in CCA. In conclusion, the present study showed that aberrant expression of B7-H4 was correlated with poorer prognosis and suppressed CD8+ tumor‑infiltrating lymphocytes in CCA.