Oncotarget

Research Papers:

Profile of differentially expressed Toll-like receptor signaling genes in the natural killer cells of patients with Sézary syndrome

Kelly C.G. Manfrere, Marina P. Torrealba, Denis R. Miyashiro, Nátalli Z. Pereira, Fabio S.Y. Yoshikawa, Luana de M. Oliveira, Jade Cury-Martins, Alberto J.S. Duarte, José A. Sanches and Maria N. Sato _

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Oncotarget. 2017; 8:92183-92194. https://doi.org/10.18632/oncotarget.21006

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Abstract

Kelly C.G. Manfrere1, Marina P. Torrealba1, Denis R. Miyashiro2, Nátalli Z. Pereira1, Fabio S.Y. Yoshikawa1, Luana de M. Oliveira1, Jade Cury-Martins2, Alberto J.S. Duarte1, José A. Sanches2,* and Maria N. Sato1,*

1Laboratory of Medical Investigation, LIM-56, Department of Dermatology, Tropical Medicine Institute of São Paulo, University of São Paulo Medical School, São Paulo, Brazil

2Cutaneous Lymphoma Clinic, Hospital das Clínicas, Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil

*These authors share the mentorship, critical revision and supervision of this study

Correspondence to:

Maria N. Sato, email: [email protected]

Keywords: Sézary syndrome, natural killer cells, Toll-like receptor 7/8, memory NK cells, differentially expressed genes

Received: July 06, 2017    Accepted: August 27, 2017    Published: September 18, 2017

ABSTRACT

Sézary syndrome (SS), an aggressive and leukemic form of cutaneous T-cell lymphoma, usually results in shortened survival. Improving innate immunity in SS by targeting natural killer (NK) cells with Toll-like receptor (TLR) agonists could be an interesting modulatory strategy. We evaluated the NK cell populations in SS patients assessing activating and inhibitory receptors expression and profiled the differential expression of TLR signaling pathway genes in unstimulated NK cells and after TLR7/8 stimulation. We observed preserved CD56bright NK cells and a low percentage of CD56dim NK cells in the peripheral blood of SS patients compared to those in the healthy control group. Both NK cell populations showed down-modulation of NKG2C and NKG2D expression, which was associated with high serum levels of the soluble form of NKG2D ligands. In contrast, an expansion of “memory” CD57+ NKG2C+ NK cells and high cytomegalovirus antibody titers were detected in SS patients. Profiling of the TLR signaling genes in NK cells from SS patients showed an abundance of differentially expressed genes (DEGs) in NK cells in the unstimulated condition, with mostly up-regulation of NFκB/JNK p38 pathway genes, but there was down-regulation of type I (IFN-α/β) and II (IFN-γ) interferon and IL-12A. After activation of NK cells with TLR7/8 agonist, the down-regulated genes correlated with the IFN response, and IL-12 became up-regulated, together with other antitumor factors. NK cell activation with a dual agonist for TLR7 and TLR8 is able to induce the expression of IFN-γ and type I IFN, which can improve immunity in SS patients.


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