PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome

Abstract

Objective: Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC).

Materials and methods: We investigated the expression of PD-1, PD-L1, CD8⁺ T cells, and CD68⁺ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry.

Results: We found that high proportion of tumor-infiltrating CD8⁺ PD-1^High within CD8⁺ PD-1⁺ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8⁺ PD-1^High in CD8⁺ PD-1⁺ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68⁺ PD-L1⁺ significantly and positively correlated with the density of CD8⁺ PD-1^High (P < 0.0001, r = 0.5927). The proportion of CD68⁺ PD-L1⁺ within CD68⁺ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68⁺ PD-L1⁺ macrophages and CD8⁺ PD-1^High T cells may cooperatively play a role in inhibiting anti-tumor immunity.

Conclusion: CD68⁺ PD-L1⁺ macrophages and CD8⁺ PD-1^High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.

Keywords: Immunotherapy; Intrahepatic cholangiocarcinoma; Programmed cell death protein ligand 1; Programmed cell death protein-1; Tumor immune micro-environment.