Abstract
BackgroundCholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis. Despite recent advances, to date there is still no established targeted therapeutic approach available. Non-surgical therapeutic agents are urgently needed, as most patients are non-eligible to surgical resection. Anti-PD-L1 therapy prevents cancer cells from evading the immune system and has emerged as a new treatment option in several cancer entities. Recently, PD-L1 expression has been analyzed in comparably small CCA patient cohorts. However, a systematic validation of different PD-L1 antibodies has not been performed in CCA so far.MethodsWe stained a tissue microarray consisting of 170 patients, including 72 intrahepatic cholangiocarcinomas (iCCAs), 57 perihilar cholangiocarcinomas (pCCAs) and 41 distal cholangiocarcinomas (dCCAs) by immunohistochemistry and evaluated PD-L1 positivity in tumor and stromal cells. We analyzed three different PD-L1 antibodies (clones 28–8, SP142, and SP263) that are frequently used and recommended for predictive diagnostic testing in other cancer types.ResultsFor PD-L1 antibody clone SP263, 5% of iCCAs, 4% of pCCAs and 3% of dCCAs exhibited PD-L1 expression on tumor cells, thereby showing the highest frequencies of PD-L1 positivity. Accordingly, highest PD-L1 positivity rates of stromal cells with 31% in iCCA, 40% in pCCA and 61% in dCCA were detected for clone SP263. Agreement of PD-L1 positivity in tumor cells was moderate for clone 28–8 and SP263 (κ = 0.44) and poor between 28-8 and SP142 (κ = 0.13), as well as SP142 and SP263 (κ = 0.11), respectively. Statistical analyses of PD-L1 expression (clone SP263) on tumor cells with clinicopathological data revealed a positive correlation with shortened overall survival in CCA patients.ConclusionsSelection of appropriate PD-L1 antibodies and careful evaluation of immunohistochemical staining patterns have a significant impact on PD-L1 testing in CCA. Clinical trials are necessary to investigate the putative beneficial effects of PD-L1 targeted immunotherapy in CCA patients.
Highlights
Cholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis
programmed cell death ligand 1 (PD-L1) is expressed on tumor cells and interacts with PD-1 on cytotoxic T-cells, leading to reduced T-cell function and thereby lower anti-tumor activity of the host’s immune system [1]
CCA subtype specific analysis for PD-L1 expression in association with patient survival showed decreased overall survival rates in Intrahepatic cholangiocarcinoma (iCCA) patients with PD-L1 positivity in > 5% of tumor cells (p = 0.02, Fig. 3b) and decreased overall survival rates by trend in Perihilar cholangiocarcinoma (pCCA) patients with PD-L1 positivity in > 5% of tumor cells (p = 0.06, Fig. 3d)
Summary
Cholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis. PD-L1 inhibitors prevent cancer cells from evading the immune system These agents have been found effective in melanoma [2,3,4], non-small cell lung cancer [4,5,6], renal cell carcinoma [4, 7] and urothelial carcinoma [8], and were approved by the Food and Drug Administration for these cancer types [9]. CCAs and biliary tract cancers have often been treated as one tumor type in the past [12], it is nowadays widely accepted that CCAs, and in particular intrahepatic and extrahepatic subtypes display significant clinical, biological, and therapeutically relevant differences, leading to the consensus that all subtypes should be regarded differentially [13, 14]. PD-L1 expression has been shown to correlate with a worse outcome in a meta-analysis including various cancer types and more than 16,000 patient samples, but CCA was not included [17]
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