Tofacitinib overcomes an IFNγ-induced decrease in NK cell-mediated cytotoxicity via the regulation of immune-related molecules in LC-2/ad.
Thorac Cancer
; 12(6): 775-782, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-33491334
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.Palabras clave
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Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Piperidinas
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Pirimidinas
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Células Asesinas Naturales
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Regulación Neoplásica de la Expresión Génica
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Interferón gamma
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Inhibidores de Proteínas Quinasas
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article