Observational Study of PD-L1, TGF-β, and Immune Cell Infiltrates in Hepatocellular Carcinoma

Frontiers in Medicine

article

Christian Ihling¹  Bartholomew Naughton²  Yue Zhang³  P. Alexander Rolfe²  Eveline Frick-Krieger¹  Luigi M. Terracciano⁴  Isabelle Dussault³ 

[1] Global Clinical Biomarkers & Companion Diagnostics;Inc., United States;Clinical Biomarkers & Companion Diagnostics Biopharma, Inc., United States;Molecular Pathology Division, Institute of Pathology, University Hospital

关键词: PD-L1;    checkpoint inhibitor;    CD8;    immune cell infiltrates;    hepatocellular carcinoma;    HCC;   

DOI  :  10.3389/fmed.2019.00015

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Introduction: Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers, with increased programed death ligand 1 (PD-L1) and transforming growth factor beta (TGF-β) activity implicated in immunosuppression. Methods: In an observational study of HCC liver samples, we determined the incidence of PD-L1 and immune cell (IC) infiltrates, and signs of TGF-β activity. HCCs were characterized by the incidence and distribution of PD-L1 + cells, and CD8 + , CD68 + , and FoxP3 + infiltrating ICs in HCC and surrounding liver. Gene expression signatures (GESs) associated with TGF-β activity and ICs were evaluated by RNAseq. Results: In non-neoplastic cirrhotic and non-cirrhotic liver, PD-L1 occurred on sinusoidal lining cells (mostly Kupffer cells), endothelial cells and ICs. In HCC, PD-L1 + tumor cells were rare. Most PD-L1 + cells were identified as ICs. CD8 + , CD68 + , and FoxP3 + ICs were associated with HCC, particularly in the invasive margin. CD8 + cell incidence correlated with PD-L1 + cells, consistent with PD-L1 being upregulated in response to pre-existing cytotoxic T-lymphocyte activity. TGFB1 mRNA levels and TGF-β activation GES correlated with the strength of the tumor-associated macrophage GES. Conclusion: Inhibition of PD-L1 + ICs and TGF-β activity and their respective immunomodulatory pathways may contribute to antitumor effects in HCC.

【 授权许可】

CC BY