RRC ID 68851
Author Okita R, Shimizu K, Nojima Y, Saisho S, Nakata M.
Title Tofacitinib overcomes an IFNγ-induced decrease in NK cell-mediated cytotoxicity via the regulation of immune-related molecules in LC-2/ad.
Journal Thorac Cancer
Abstract BACKGROUND:Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD-L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ-induced PD-L1 is one of the major mechanisms by which cancer cells escape host immunity.
METHODS:Here, we found that the NSCLC cell line, LC-2/ad, has a unique character; the PD-L1 expression in these cells is up-regulated by both IFNγ and epidermal growth factor (EGF).
RESULTS:Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC-2/ad cells. IFNγ-induced PD-L1, but not EGF-induced PD-L1, was clearly blocked by the JAK-STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell-activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell-mediated cytotoxicity in LC-2/ad cells, which was, however, blocked by tofacitinib.
CONCLUSIONS:Taken together, our study shows that tofacitinib blocks the IFNγ-induced transformation from an NK cell-sensitive phenotype to an NK cell-resistant one in IFNγ-reacted LC-2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ-induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.
Volume 12(6)
Pages 775-782
Published 2021-3-1
DOI 10.1111/1759-7714.13847
PMID 33491334
PMC PMC7952785
MeSH Gene Expression Regulation, Neoplastic / drug effects* Humans Interferon-gamma / adverse effects* Killer Cells, Natural / immunology* Peptide Fragments / adverse effects* Piperidines / pharmacology Piperidines / therapeutic use* Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use* Pyrimidines / pharmacology Pyrimidines / therapeutic use*
IF 2.524
Human and Animal Cells A549 RERF-LC-AI(RCB0444) RERF-LC-KJ(RCB1313)