RRC ID 52447
Author Homma S, Hayashi K, Yoshida K, Sagawa Y, Kamata Y, Ito M.
Title Nafamostat mesilate, a serine protease inhibitor, suppresses interferon-gamma-induced up-regulation of programmed cell death ligand 1 in human cancer cells.
Journal Int Immunopharmacol
Abstract Programmed cell death ligand-1 (PD-L1) plays a pivotal role in the suppression of antitumour immunity by binding to programmed cell death-1 (PD-1) on tumouricidal cytotoxic T lymphocytes (CTLs), rendering them inactive. As blockade of PD-1/PD-L1 interaction by the monoclonal antibodies induced effective T cell-mediated antitumour response, suppression of PD-L1 expression in tumour cells by the chemical agent might contribute to treatment against malignant tumours. Nafamostat mesilate (NM), a serine protease inhibitor that is frequently used in the clinic, potently suppressed interferon-gamma (IFN-gamma)-induced up-regulation of PD-L1 in cultured human lung cancer cells (HLC-1) at both the messenger RNA (mRNA) and protein levels. Interestingly, suppression of IFN-gamma-induced up-regulation of human leukocyte antigen (HLA)-ABC by NM was limited, suggesting that NM did not block CTL responses to tumour cells. NM treatment did not affect the activation status of signal transducer and activator of transcription (STAT) 1 or the induction of interferon regulatory factor (IRF)-1 expression in IFN-gamma-treated HLC-1 cells. Although NM treatment promoted the phosphorylation of extracellular signal-regulated kinases (Erk) 1/2, an Erk inhibitor, U0126, could not reverse the suppression of PD-L1 up-regulation by IFN-gamma. Suppression of IFN-gamma-induced up-regulation of PD-L1 by NM was not associated with the inhibition of nuclear factor kappa B (NF-kB) or protease-activated receptor (PAR)-1 pathway. Besides HLC-1 cells, NM suppressed IFN-gamma-induced PD-L1 up-regulation in three human pancreatic cancer cell lines. NM could potentiate the antitumour effect of cancer vaccines or immune checkpoint inhibitors by preventing IFN-gamma-induced PD-L1 up-regulation and blocking immune checkpoint suppression.
Volume 54
Pages 39-45
Published 2018-1-1
DOI 10.1016/j.intimp.2017.10.016
PII S1567-5769(17)30394-6
PMID 29100036
MeSH Adenocarcinoma / drug therapy* B7-H1 Antigen / genetics B7-H1 Antigen / metabolism* CD8-Positive T-Lymphocytes / immunology* Cancer Vaccines Cell Line, Tumor Guanidines / pharmacology* HLA Antigens / metabolism Humans Immunosuppression Interferon-gamma / metabolism Lung Neoplasms / drug therapy* Pancreatic Neoplasms / drug therapy* Serine Proteinase Inhibitors / pharmacology* Up-Regulation
IF 3.943
Times Cited 6
Human and Animal Cells HLC-1(RCB0083)