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Oncoimmunology. 2014 Nov 14;3(8):e948705. eCollection 2014.

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

Author information

1
Apoptosis, Immunity & Cancer Group; Department of Biochemistry and Molecular and Cell Biology ; University of Zaragoza and Aragón Health Research Institute (IIS Aragón) ; Zaragoza, Spain.
2
INSERM U1040; Université de Montpellier 1; UFR Médecine ; Montpellier, France.
3
CNRS UMR 5235; Université de Montpellier II; Place Eugene Bataillon ; Montpellier, France.
4
Immune Effector Cells Group; IIS Aragón; Biomedical Research Center of Aragón (CIBA); Nanoscience Institute of Aragon (INA); Zaragoza, Spain ; Aragón I+D Foundation (ARAID) ; Zaragoza, Spain.
5
INSERM U1040; Université de Montpellier 1; UFR Médecine ; Montpellier, France ; Institut de Recherche en Biothérapie (IRB); CHU Montpellier ; Montpellier, France.

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.

KEYWORDS:

CDK8, cyclin-dependent kinase 8; CXCL10; CXCL10, (C-X-C motif) ligand 10/CXCL10; FCS, fetal calf serum; IFN-α, IL-15; IFNA1; IFNα, interferon-α; IFNγ, interferon-γ, IFNG; IL-15, interleukin-15/IL15; MACS, magnetic cell separation; MEF, murine embryonic fibroblast; MHC-I, major histocompability complex class I/MHC-I; NK cells; NK, natural killer; PI3K, phosphatidylinositol-3-kinase; PKC-θ; PKC-θ, protein kinase C-θ, PRKCQ; PLC, phospholipase-C; Poly I:C, poly-inosinic:cytidilic acid; RT-PCR, real-time polymerase chain reaction; STAT-1, signal transducer and activator of transcription-1/STAT1.; mAb, monoclonal antibody

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