Tofacitinib Overcomes An Ifn Gamma-Induced Decrease In Nk Cell-Mediated Cytotoxicity Via The Regulation Of Immune-Related Molecules In Lc-2/Ad

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 IFN gamma, which is secreted by T cells and NK cells. Importantly, IFN gamma-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 IFN gamma and epidermal growth factor (EGF).Results Comparative analysis of the cell signaling pathway showed that IFN gamma activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC-2/ad cells. IFN gamma-induced PD-L1, but not EGF-induced PD-L1, was clearly blocked by the JAK-STAT inhibitor tofacitinib. Interestingly, IFN gamma 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 IFN gamma 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 IFN gamma-induced transformation from an NK cell-sensitive phenotype to an NK cell-resistant one in IFN gamma-reacted LC-2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFN gamma-induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.