AUTHOR=Ihling Christian , Naughton Bartholomew , Zhang Yue , Rolfe P. Alexander , Frick-Krieger Eveline , Terracciano Luigi M. , Dussault Isabelle TITLE=Observational Study of PD-L1, TGF-β, and Immune Cell Infiltrates in Hepatocellular Carcinoma JOURNAL=Frontiers in Medicine VOLUME=6 YEAR=2019 URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2019.00015 DOI=10.3389/fmed.2019.00015 ISSN=2296-858X ABSTRACT=

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.