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

Lingyu Tian,Jiaqiang Ma,Xiaoying Wang,Longzi Liu,Lijie Ma,Danjun Song,Bohao Zheng,Qiang Gao,Kang Song,Zhao Zhang,Yining Wang

doi:10.1186/s12957-020-02082-5

Abstract

ObjectiveImmunotherapy 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 methodsWe 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.ResultsWe found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High 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-1High (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-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity.ConclusionCD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.

Highlights

Intrahepatic cholangiocarcinoma (ICC), a highly aggressive biliary epithelial malignancy, roughly accounts for 10–15% of primary liver cancer, with an increasing disease morbidity and mortality worldwide [1, 2]
Synopsis This research addressed the prognostic value of programmed cell death (PD)-1/PDL1 expression on CD8+ T cells and CD68+ macrophages in intrahepatic cholangiocarcinoma
A previous study has demonstrated that tumor infiltrating lymphocytes (TILs) are associated with prognosis in patients with ICC, and CD8+ infiltration is associated with better survival and lower recurrence [13]

Summary

Introduction

Intrahepatic cholangiocarcinoma (ICC), a highly aggressive biliary epithelial malignancy, roughly accounts for 10–15% of primary liver cancer, with an increasing disease morbidity and mortality worldwide [1, 2]. Hepatectomy remains the only potentially curative treatment for ICC patients, but the clinical outcomes of ICC are dismal, with the 5-year postoperative overall survival (OS) rate ranging from 20 to 40% [5, 6]. For those unresectable tumors, the current treatment effects on tumor control in patients remain limited. Immunotherapy that normalizes the immune response in the tumor microenvironment (TME), especially through targeting programmed cell death (PD) pathways, has been shown to achieve high response rates in several malignant tumors [10]. Some studies have reported that high levels of tumor-associated macrophages (TAMs) are associated with better survival in patients with ICC [14], while others showed opposite trends [15]

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Conclusion