Tofacitinib overcomes an IFNγ‐induced decrease in NK cell‐mediated cytotoxicity via the regulation of immune‐related molecules in LC‐2/ad

• Published in: Thoracic cancer Vol. 12; no. 6; pp. 775 - 782
• Main Authors: Okita, Riki, Shimizu, Katsuhiko, Nojima, Yuji, Saisho, Shinsuke, Nakata, Masao
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01-03-2021; John Wiley & Sons, Inc; Wiley
• Subjects: Cell culture; Cloning; Cytotoxicity; Epidermal growth factor; Experiments; Flow cytometry; IFNγ; Immunotherapy; Infrared imaging systems; JAK‐STAT pathway; Kinases; Lung cancer; Medical research; NK cell; nonsmall cell lung cancer (NSCLC); Original; Proteins; tofacitinib; IFNγ; nonsmall cell lung cancer (NSCLC); JAK-STAT pathway; NK cell; tofacitinib
• ISSN: 1759-7706; 1759-7714
• DOI: 10.1111/1759-7714.13847

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.
The JAK‐STAT inhibitor 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 could be adapted to the limited number of NSCLC patients.