PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma.

Jacqueline Fontugne,Alain Luciani,Philippe Compagnon,Jérémy Augustin,Christophe Tournigand,Anaïs Pujals,Benoit Rousseau,Daniel Azoulay,Julien Calderaro,Daniel Cherqui,Jean-Michel Pawlotsky

doi:10.18632/oncotarget.15602

Abstract

Cholangiocarcinoma is an aggressive biliary neoplasm lacking effective therapeutic agents. Immunotherapies targeting the PD-L1/PD-1 immune checkpoint have shown encouraging results in solid and hematologic cancers in clinical trials. Response to these immunomodulators is correlated with PD-L1 expression. Our goal was to characterize PD-L1 expression in intra-hepatic (iCCA) and perihilar (pCCA) cholangiocarcinomas, and to correlate our results with clinicopathological features, density of tumor-infiltrating lymphocytes (TILs) and PD-1 expression.A series of 58 iCCAs and 41 pCCAs was included in the study. PD-L1, PD-1 and CD3 expression was investigated using immunohistochemistry. Density of TILs was evaluated by immunohistochemistry using a quantitative score of CD3-stained intratumoral lymphocytes.PD-L1 expression by neoplastic cells was observed in 9 cases (9%, 5 iCCAs and 4 pCCAs). PD-L1 positive inflammatory cell aggregates were identified in 46% (n = 46) of the cases (31 iCCAs and 15 pCCAs). PD-L1 expression by either neoplastic or inflammatory cells was associated to high density of CD3-positive TILs (p = 0.01 and p = 0.005, respectively). The number of PD-L1 positive inflammatory cell aggregates was higher in tumors with high PD-1 expression (p < 0.0001).Altogether, PD-L1 in iCCA and pCCA is mainly expressed in tumors with high density of TILs. Our results suggest that CCAs with dense intratumoral lymphocytic infiltration might represent good candidates for PD-L1/PD-1 blocking agents.

Highlights

Cholangiocarcinomas represent a heterogeneous group of cancers derived from epithelial biliary cells
Our results suggest that CCAs with dense intratumoral lymphocytic infiltration might represent good candidates for Programmed-death Ligand 1 (PD-L1)/Programmedwww.impactjournals.com/oncotarget death-1 (PD-1) blocking agents
Cholangiocarcinoma is a highly aggressive neoplasm characterized by the lack of effective therapy and a dismal prognosis

Summary

Introduction

Cholangiocarcinomas represent a heterogeneous group of cancers derived from epithelial biliary cells. They are classified, according to their anatomic localization on the biliary tree, into intra-hepatic (iCCA), perihilar (pCCA) or distal cholangiocarcinomas [1]. Cholangiocarcinomas are characterized by high-level resistance to conventional anticancer agents and poor clinical outcome [2]. The only curative treatment, is hampered by a high rate of tumor recurrence and a low overall 5-year survival rate [3]. New treatment strategies for cholangiocarcinoma represent an urgent unmet need. Clinical trials using monoclonal antibodies targeting immune checkpoint regulators, such as Programmedwww.impactjournals.com/oncotarget death-1 (PD-1) or its major ligand, Programmed-death Ligand 1 (PD-L1), showed promising results in various hematologic and solid cancers [4]. An objective response or prolonged disease stabilization were obtained in patients with advanced melanoma, bladder urothelial carcinoma, Hodgkin’s lymphoma and renal cell, colorectal or non small-cell lung carcinomas [5,6,7,8,9,10]

Objectives

Methods

Results

Conclusion