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

Li-Chun Lu; Yi-Hsuan Lee; Chun-Jung Chang; Chia-Tung Shun; Chih-Yeu Fang; Yu-Yun Shao; Tsung-Hao Liu; Ann-Lii Cheng; Chih-Hung Hsu

doi:10.1159/000489021

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

Liver Cancer. 2019 Mar;8(2):110-120. doi: 10.1159/000489021. Epub 2018 Jun 15.

Authors

Li-Chun Lu^{1

2

3}, Yi-Hsuan Lee⁴, Chun-Jung Chang¹, Chia-Tung Shun^{4

5}, Chih-Yeu Fang⁶, Yu-Yun Shao^{1

2

3}, Tsung-Hao Liu^{2

7}, Ann-Lii Cheng^{1

2

8

3}, Chih-Hung Hsu^{1

2}

Affiliations

¹ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
² Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
³ National Taiwan University Cancer Center, Taipei, Taiwan.
⁴ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Department of Forensic Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Pathology, Wan Fan Hospital, Taipei Medical University, Taipei, Taiwan.
⁷ Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
⁸ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

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.

Keywords: Hepatocellular carcinoma; Macrophage; Programmed death-ligand 1; Sorafenib; Tumor microenvironment.