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

ABSTRACT: Introduction: Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers, with increased programed death ligand 1 (PD-L1) and transforming growth factor beta (TGF-?) 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-? 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-? 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-? activation GES correlated with the strength of the tumor-associated macrophage GES. Conclusion: Inhibition of PD-L1+ ICs and TGF-? activity and their respective immunomodulatory pathways may contribute to antitumor effects in HCC.

SUBMITTER: Ihling C 

PROVIDER: S-EPMC6375852 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature