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

Publisher: Wiley Publishing Asia Pty Ltd Country of Publication: Singapore NLM ID: 101531441 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1759-7714 (Electronic) Linking ISSN: 17597706 NLM ISO Abbreviation: Thorac Cancer Subsets: MEDLINE

Publication: November 2012- : Singapore : Tianjin : Wiley Publishing Asia Pty Ltd ; Tianjin Lung Cancer Institute
Original Publication: Richmond, Vic. : Tianjin : Blackwell Pub. Asia Pty Ltd. ; Tianjin Lung Cancer Institute

Gene Expression Regulation, Neoplastic/*drug effects ; Interferon-gamma/*adverse effects ; Killer Cells, Natural/*immunology ; Peptide Fragments/*adverse effects ; Piperidines/*therapeutic use ; Protein Kinase Inhibitors/*therapeutic use ; Pyrimidines/*therapeutic use; Humans ; Piperidines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology

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.
(© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

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This work was supported by the Japan Society for the Promotion of Science (JSPS) Kakenhi Grant (25462189, 16K10696, and 19K09298) to Riki Okita and the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology (S1291010) to Masao Nakata

Keywords: IFNγ; JAK-STAT pathway; NK cell; nonsmall cell lung cancer (NSCLC); tofacitinib

0 (Peptide Fragments)
0 (Piperidines)
0 (Protein Kinase Inhibitors)
0 (Pyrimidines)
0 (interferon gamma (1-39))
82115-62-6 (Interferon-gamma)
87LA6FU830 (tofacitinib)

Date Created: 20210125 Date Completed: 20211119 Latest Revision: 20211119

20250114

PMC7952785

10.1111/1759-7714.13847

33491334