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.

Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti–PD-1/PD-L1 therapy

“…PD-L1 expression was more likely to be seen on peri-tumoral immune cells at tumor edges (n=10) than on tumor cells (n=5). Like other tumor types, poorly-differentiated NECs in our study frequently expressed PD-1 on immune cells, including tumor infiltrating lymphocytes and peritumoral inflammatory cells at tumor edges[11–14]. Unexpectedly, we also found that tumor cells in 6 of 37 cases expressed PD-1 at least focally.…”

Programmed cell death ligand‐1 (PD‐L1) expression in extrahepatic biliary tract cancers: a comparative study using 22C3, SP263 and E1L3N anti‐PD‐L1 antibodies

“…In this clinical trial, PD‐L1 positivity was defined as staining in 1% of cells in tumour nests or PD‐L1‐positive bands in the stroma as determined with the 22C3 assay . However, data regarding PD‐L1 expression status in extrahepatic biliary tract cancers are still limited, and the frequency of PD‐L1 expression in bile duct cancer has varied among studies (Table ) . This variability may be explained by multiple factors, including assay method, interpretation method, specimen type (biopsy; surgically resected specimen), and patient demographics (including tumour stage) …”

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…The most-studied biomarker to date is the PD-1 ligand, PD-L1; any expression of PD-L1 on tumour cells, and/or higher levels of tumour PD-L1 expression have both been associated with sensitivity to immune-checkpoint- inhibitor monotherapy in some tumour types, including melanoma and non-small-cell lung cancer (NSCLC), but with conflicting results in other diseases 160–162 . In studies of small numbers of cholangiocarcinoma tumour samples ( n = 54–99), PD-L1 expression has been reported in 9–72% of specimens 163–165 , and on 46–63% of immune cells within the tumour microenvironment 164,165 . These data indicate that a substantial proportion of cholangiocarcinomas might be amenable to therapy with PD-1 or PD-L1 inhibitors.…”