PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma

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.

Keywords: PD-1; PD-L1; cholangiocarcinoma; immunotherapy.

Figure 1. PD-L1 expression in cholangiocarcinoma

Poorly differentiated iCCA case showing a massive architectural pattern and no obvious glandular differentiation (hematein-eosin-saffron, X200) (A), membranous PD-L1 expression by the vast majority of neoplastic cells in this tumor area (X200) (B), and clusters of PD-L1-positive inflammatory cells (X200) (C). Well-differentiated iCCA case characterized by a glandular architectural pattern (hematein-eosin-saffron, X200) (D), no PD-L1 expression by neoplastic cells (X200) (E) or by inflammatory cells (X200) (F).

Figure 2. PD-L1 expression by inflammatory cells is significantly higher in PD-1 high tumors

Number of PD-L1 positive inflammatory cell aggregates in tumors with low and high PD-1 expression (p < 0.0001) (A). Representative micrographs of high (B) and low (C) PD-1 expression (X400).