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

Author(s)

Manfrere, Kelly C. G. ^[1] ; Torrealba, Marina P. ^[1] ; Miyashiro, Denis R. ^[2] ; Pereira, Natalli Z. ^[1] ; Yoshikawa, Fabio S. Y. ^[1] ; Oliveira, Luana de M. ^[1] ; Cury-Martins, Jade ^[2] ; Duarte, Alberto J. S. ^[1] ; Sanches, Jose A. ^[2] ; Sato, Maria N. ^[1]

Affiliation

^[1] Univ Sao Paulo, Med Sch, Lab Med Invest, Dept Dermatol, Trop Med Inst Sao Paulo, LIM 56, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Med Sch, Cutaneous Lymphoma Clin, Hosp Clin, Dept Dermatol, Sao Paulo - Brazil

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 54, p. 92183-92194, NOV 3 2017.
• Web of Science Citations: 0

Abstract

Sezary 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 CD56(bright) NK cells and a low percentage of CD56(dim) 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 NF kappa B/JNK p38 pathway genes, but there was down-regulation of type I (IFN-alpha/beta) and II (IFN-gamma) 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-gamma and type I IFN, which can improve immunity in SS patients. (AU)

• FAPESP's process: 14/04865-9 - Activation of cytotoxic response mediated by polyfunctional natural killer cells and t CD8+ cells induced by Toll-like-receptors agonists in the mycosis fungoides and Sézary syndrome
• Grantee: José Antonio Sanches Junior
• Support Opportunities: Regular Research Grants