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Tofacitinib overcomes an IFNγ-induced decrease in NK cell-mediated cytotoxicity via the regulation of immune-related

Riki Okita1,2, Katsuhiko Shimizu1, Yuji Nojima1

  • 1Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki, Japan.

Thoracic Cancer
|January 25, 2021
PubMed
Abstract

Insights

Tofacitinib blocks interferon-gamma (IFNγ)-induced programmed cell death-1 ligand 1 (PD-L1) expression in non-small cell lung cancer (NSCLC) cells. This inhibition may overcome tumor immune escape mediated by IFNγ, offering a potential therapeutic strategy for some NSCLC patients.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis show promise in non-small cell lung cancer (NSCLC).
  • Interferon-gamma (IFNγ) is a key inducer of PD-L1, contributing to cancer immune evasion.
  • Understanding PD-L1 regulation is crucial for enhancing anti-tumor immunity.

Purpose of the Study:

  • To investigate the unique regulation of PD-L1 expression in the LC-2/ad NSCLC cell line.
  • To elucidate the signaling pathways involved in IFNγ and epidermal growth factor (EGF)-induced PD-L1 expression.
  • To evaluate the potential of JAK-STAT inhibition in overcoming IFNγ-mediated immune escape.

Main Methods:

  • Comparative analysis of signaling pathways activated by IFNγ and EGF in LC-2/ad cells.
  • Treatment with the JAK-STAT inhibitor tofacitinib to assess its effect on PD-L1 expression.
  • Assessment of NK cell-activating ligands, MHC class I expression, and NK cell-mediated cytotoxicity.

Main Results:

  • IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and S6K in LC-2/ad cells.
  • Tofacitinib specifically blocked IFNγ-induced PD-L1, but not EGF-induced PD-L1.
  • IFNγ treatment reduced NK cell-activating ligands and increased MHC class I, promoting NK cell resistance, which was reversed by tofacitinib.

Conclusions:

  • Tofacitinib effectively blocks IFNγ-induced PD-L1 upregulation and the subsequent shift towards NK cell resistance in NSCLC cells.
  • This suggests tofacitinib holds promise for overcoming IFNγ-driven tumor immune escape in a subset of NSCLC patients.
  • Further investigation is warranted to explore the therapeutic potential of tofacitinib in NSCLC immunotherapy.
Keywords:
IFNγJAK-STAT pathwayNK cellnonsmall cell lung cancer (NSCLC)tofacitinib

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