Increased Expression of Programmed Death-Ligand 1 in Infiltrating Immune Cells in Hepatocellular Carcinoma Tissues after Sorafenib Treatment

Abstract

Objective: Programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment (TME) has been reported to be related to prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC is unclear. Patients and Methods: Patients with HCC who received sorafenib for advanced disease at National Taiwan University Hospital, Taipei, Taiwan, and who had paired HCC tissues obtained before and after sorafenib treatment were included in the study group. HCC patients not treated with sorafenib who had paired primary and recurrent or metastatic tissues were identified as the reference group. The membrane PD-L1 staining, detected by immunohistochemistry (IHC) using SP142 antibody, was semiquantitatively scored in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). Additional IHC assays were employed to characterize the PD-L1-expressing ICs. Results: Twenty-three advanced HCC patients with pre- and post-sorafenib paired HCC tissues were included in the study group. The median duration of sorafenib treatment was 4.3 months (range: 1.3–18.7). PD-L1 expression in ICs was significantly higher in post-sorafenib HCC tissues than in pre-sorafenib HCC tissues (pre-sorafenib vs. post-sorafenib IHC 0/1/2/3: 11/5/5/2 vs. 5/5/2/11, p = 0.016). However, PD-L1 expression in TCs was not significantly different between pre- and post-sorafenib tissues (IHC 0/1/2/3: 19/2/0/2 vs. 14/5/0/4, p = 0.094). In the reference group of 44 patients not treated with sorafenib, PD-L1 expression in ICs and TCs was not significantly different between the paired primary and metastatic HCC tissues. By performing IHC double staining with PD-L1 and CD68, we found the PD-L1-expressing ICs were mainly CD68-positive macrophages. PD-L1 expression levels of pre- and post-sorafenib tissues were not associated with patients’ overall survival or duration of sorafenib treatment. Conclusions: PD-L1 expression in ICs was significantly increased in post-sorafenib HCC tissues. The mechanisms and clinical significance of this observation warrants further investigation.

Immune Checkpoint Blockade Mediated by a Small‐Molecule Nanoinhibitor Targeting the PD‐1/PD‐L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer

“…It was found that PD‐L1 expression on 4T1 cells was higher in post‐treatments than in pretreatments. Previous work also indicated that PD‐L1 expression on the tumor cell surface was higher in post‐treatment than that in pretreatment . All samples regardless of treatment expressed PD‐L1 (Figure b).…”

Immune-based therapies for hepatocellular carcinoma

“…The expression of PD-L1 itself is strongly placed under the transcriptional regulation of hypoxia inducible factor 1-alpha [129]. In HCC, sorafenib therapy induces tumoural PD-L1 overexpression [130], and pre-clinical evidence in mouse models suggests this to correlate with T-reg accumulation and M2-macrophage polarisation through hypoxia, drawing a translationally appealing rationale for combination therapy [131]. Inhibition of tumour angiogenesis, and in particular VEGF aids normalisation of the endothelial barrier by regulating key adhesion molecules for immune cell homing to the tumour.…”

Immune checkpoint inhibitors for hepatocellular carcinoma

“…32 This suggests that sorafenib treatment may recruit T cells to the tumor and then elicit PD-L1 expression (possibly by expression of interferon-γ). For example, it has been reported that PD-L1 expression in HCC samples increases after treatment with sorafenib.…”

“…For example, it has been reported that PD-L1 expression in HCC samples increases after treatment with sorafenib. 32 This suggests that sorafenib treatment may recruit T cells to the tumor and then elicit PD-L1 expression (possibly by expression of interferon-γ). To the best of our knowledge, the mechanism of this change remains to be elucidated and may be related to the type of cell death induced by sorafenib or the inhibition of specific tyrosine kinases such as vascular endothelial growth factor receptor.…”