PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma

Abstract

Purpose More effective therapy is needed for intrahepatic cholangiocarcinoma (ICC). The encouraging clinical results obtained with checkpoint molecule-specific monoclonal antibodies (mAb) have prompted us to investigate whether this type of immunotherapy may be applicable to ICC. The aims of this study were to determine whether (i) patients mount a T-cell immune response to their ICC, (ii) checkpoint molecules are expressed on both T cells and tumor cells, and (iii) tumor cells are susceptible to recognition by cognate T cells. Experimental Design Twenty-seven ICC tumors were analyzed for (i) lymphocyte infiltrate, (ii) HLA class I and HLA class II expression, and (iii) PD-1 and PD-L1 expression by T cells and ICC cells, respectively. The results of this analysis were correlated with the clinicopathologic characteristics of the patients investigated. Results Lymphocyte infiltrates were identified in all tumors. PD-L1 expression and HLA class I antigen expression by ICC cells was observed in 8 and 11, respectively, of the 27 tumors analyzed. HLA class I antigen expression correlated with CD8+ T-cell infiltrate. Furthermore, positive HLA class I antigen expression in combination with negative/rare PD-L1 expression was associated with favorable clinical course of the disease. Conclusions ICC patients are likely to mount a T-cell immune response against their own tumors. Defects in HLA class I antigen expression in combination with PD-L1 expression by ICC cells provide them with an immune escape mechanism. This mechanism justifies the implementation of immunotherapy with checkpoint molecule-specific mAbs in patients bearing ICC tumors without defects in HLA class I antigen expression.

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…In addition, the expression in tumour cells of the specific uptake transporter for bile acids, the apical sodium-dependent bile acid transporter (ASBT), has suggested the possibility of using cytostatic bile acid derivatives, such as the ursodeoxycholic acid-cisplatin conjugate BAMET-UD2, in targeted chemotherapy for CCA 270 . In 2015, the rationale for immunotherapy with checkpoint-molecule-specific monoclonal antibodies in patients bearing iCCA without defects in HLA class I antigen expression has been provided 271 but, so far, no clinical trial has been performed. Crucially, it must be underscored that the management of CCAs should only be undertaken in dedicated tertiary units with access to multidisciplinary approaches.…”

Targeting cholangiocarcinoma

“…Upregulation of PD-1/PD-L1 was demonstrated in a different set of intrahepatic CCA [58]. Dysregulation of immune checkpoint molecules was associated with less differentiated histology, more advanced tumor stage and worse outcome while HLA 1 overexpression seems to have inverse effect [59]. There is very few data on clinical use of immune therapeutics in CCA.…”

Systemic Therapy of Cholangiocarcinoma

“…Here, the median PFS was 156 days and the OS 380 days. It was also shown that programmed cell death ligand 1 (PD-L1) and human leukocyte antigen (HLA) class I is expressed in human intrahepatic CC [59]. The authors confirmed that positive HLA class I expression in combination with negative/low PD-L1 expression was associated with better clinical disease and that their findings support the usage of immunotherapeutic checkpoint inhibitors.…”