Programmed death ligand I expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8+T-cell immune responses

Background: Agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 immune checkpoint exhibited promising clinical outcomes in a variety of malignant tumors, including intrahepatic cholangiocarcinoma (ICC). However, the relationship between PD-L1 expression and CD8(+)T-cell immune responses is not well defined in ICC. Patients and methods: We investigated PD-L1 expression immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 192 ICC patients undergoing curative resection and correlated our results with the clinicopathologic features and prognosis. We also quantified CD8(+)T-cell infiltration in ICC specimens and evaluated the relationship between PD-L1 expression and CD8(+) T-cell infiltration. After incubating human ICC cell lines (HCCC9810 and RBE) with interferon (IFN)-gamma, we measured the PD-L1 expression of these ICC cells by Western blot and flow cytometry. Results: Only 34 patients (17.7%) showed >= 5% membranous PD-L1 expression on tumor cells, and tumoral PD-L1 overexpression (>= 5%) was significantly associated with superior overall survival (P=0.012) and disease-free survival (P=0.018). A significant positive association was found between PD-L1 expression and the presence of CD8(+)T-cells. In fresh frozen ICC specimens, IFN-gamma was found to be significantly correlated with PD-L1 and CD8A gene expression, as evaluated by reverse transcription-polymerase chain reaction. Moreover, stimulation of the HCCC9810 and RBE cells with recombinant IFN-gamma, secreted by CD8(+)T-cells rapidly induced PD-L1 upregulation in these cell lines in vitro. Conclusion: Tumor PD-L1 overexpression is mainly stimulated by activated CD8(+)T-cells pre-existing in the ICC microenvironment, and PD-L1 is a favorable prognostic factor for the patients. These observations suggest that anti-PIMA /programmed death receptor 1 therapy may benefit ICC patients with tumor cell PD-Ll expression and the presence of CD8(+)T-cell, IFN-gamma.