Relationship Between PD-L1 Expression and CD8+ T-cell Immune Responses in Hepatocellular Carcinoma

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Abstract
As PD-1/PD-L1 immune checkpoint inhibitors exhibited promising clinical outcomes in various types of solid tumors, PD-1/PD-L1 blockades have been explored for the treatment of hepatocellular carcinoma (HCC). However, the association of PD-L1 with antitumor immunoregulation is not clearly defined in HCC. Here, we evaluated the characteristics of PD-L1 expression, CD8+ T-cell infiltration and their relationship in HCC. A total of 411 resected tumor specimens from HCC patients were immunostained for PD-L1 and CD8. Only 78 (19%) cases showed ≥5% membranous PD-L1 expression on tumor cells, although a significantly positive correlation was found between PD-L1 expression and CD8+ T-cell densities. Moreover, patients with higher tumor PD-L1 expression also showed a higher hepatitis B virus load, which was also related to increased CD8 infiltration. Survival analysis suggested that both tumor and stroma PD-L1 status did not significantly affect overall survival or recurrence-free survival in patients. Although high CD8+ T-cell density was overall associated with better overall survival and recurrence-free survival, its favorable prognostic value was eliminated by high tumor PD-L1 expression. Further flow cytometric and enzyme-linked immunosorbent assay (ELISA) results from the coculture of HCC cell lines with specific CD8+ cytotoxic T lymphocytes (CTLs) demonstrated that CD8+ CTLs remarkably upregulated PD-L1 expression on tumor cell lines by HLA class-I specificity, and the overexpression of tumor PD-L1 impaired interferon-γ secretion by CD8+ CTLs in a negative feedback regulation mechanism. In conclusion, our findings reveal an interaction between PD-L1 expression and CD8+ T-cell immunity in HCC, although PD-L1 is not a prognostic factor for the patients.

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