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IFNα signaling through PKC-θ is essential for antitumor NK cell function

Abstract : We have previously shown that the development of a major histocompatibility complex class I (MHC-I)-deficient tumor was favored in protein kinase C-θ knockout (PKC-θ-/-) mice compared to that occurring in wild-type mice. This phenomenon was associated with scarce recruitment of natural killer (NK) cells to the tumor site, as well as impaired NK cell activation and reduced cytotoxicity ex vivo. Poly-inosinic:cytidylic acid (poly I:C) treatment activated PKC-θ in NK cells depending on the presence of a soluble factor produced by a different splenocyte subset. In the present work, we sought to analyze whether interleukin-15 (IL-15) and/or interferon-α (IFNα) mediate PKC-θ-dependent antitumor NK cell function. We found that IL-15 improves NK cell viability, granzyme B expression, degranulation capacity and interferon-γ (IFNγ) secretion independently of PKC-θ. In contrast, we found that IFNα improves the degranulation capability of NK cells against target cancer cells in a PKC-θ-dependent fashion both ex vivo and in vivo. Furthermore, IFNα induces PKC-θ auto-phosphorylation in NK cells, in a signal transduction pathway involving both phosphatidylinositol-3-kinase (PI3K) and phospholipase-C (PLC) activation. PKC-θ dependence was further implicated in IFNα-induced transcriptional upregulation of chemokine (C-X-C motif) ligand 10 (CXCL10), a signal transducer and activator of transcription-1 (STAT-1)-dependent target of IFNα. The absence of PKC-θ did not affect IFNα-induced STAT-1 Tyr701 phosphorylation but affected the increase in STAT-1 phosphorylation on Ser727, attenuating CXCL10 secretion. This connection between IFNα and PKC-θ in NK cells may be exploited in NK cell-based tumor immunotherapy.
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https://hal.umontpellier.fr/hal-03108492
Contributeur : Odile Hennaut <>
Soumis le : mercredi 13 janvier 2021 - 11:20:25
Dernière modification le : mardi 19 janvier 2021 - 11:52:02
Archivage à long terme le : : mercredi 14 avril 2021 - 18:28:29

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Natalia Comet, Juan Ignacio Aguilo, Moeez Rathoré, Elena Catalán, Johan Garaude, et al.. IFNα signaling through PKC-θ is essential for antitumor NK cell function. OncoImmunology, Taylor & Francis, 2014, 3 (8), pp.e948705. ⟨10.4161/21624011.2014.948705⟩. ⟨hal-03108492⟩

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