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

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.

Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020

“…Recently, an analysis of NK cells in peripheral blood showed no significant difference in the number of NK cells in CTCL versus healthy individuals [58]. This is in contrast with previous reports of decreased NK cell numbers in SS patients that suggested that their function may be increased by Toll-like receptor (TLR) stimulation [59]. On the other hand, higher numbers of circulating NK cells have been correlated with a poorer prognosis both in MF and in SS [58] and related to findings in another Th2-mediated disease, i.e., atopic dermatitis (AD), where NK dysregulation contributed to AD pathogenesis [60].…”

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome

“…The NKG2D is the main activating receptor of the NK cells, and it binds to major histocompatibility complex (MHC) class I homologs (MICA and MICB) and UL-16 binding proteins (ULPB)-1 to 5, that function as signals of cellular stress [57,58]. Upon binding to NKG2D ligand (NKG2DL) expressed in malignant cells, the NK cells attack by degranulation of perforin and granzyme and production of IFN-γ and TNF-α [14].…”

“…Thus, these altered NK cells may be recognized by tumor-naïve NK cells and are killed (Figure 3) [59]. Other mechanisms that favor immune escape by malignant cells, besides the trogocytosis, are the down-regulation of NKG2D observed in NK cells from SS patients [58], and the reduced number of total NK cells and the cytolytic CD56 dim CD16 bright NK cells, while the immunoregulatory CD56 bright CD16 dim NK cells are preserved [60]. The downregulation of NKG2D may be due to TGF-β and metalloproteinases [61].…”

Micose fungoide e síndrome de Sézary: caracterização demográfica, clínica, histopatológica, imunopatológica, molecular, laboratorial e evolutiva de coorte observada no ambulatório de linfomas

“…Portanto, não se sabe até que ponto o estímulo ao sistema imune levando à neutrofilia na SS leva a uma resposta realmente efetiva (Fierro et al, 2011;Manfrere et al, 2017;Torrealba et al, 2017). Além disso, estudos mostram que a relação neutrófilos/linfócitos no sangue periférico pode estar aumentada em diversas neoplasias malignas hematológicas e sólidas (Cengiz et al, 2017).…”

“…Há também uma redução nos linfócitos NK (CD16+CD56+), e aumento da expressão de CD25 na SS. Além dos níveis mais baixos de células T citotóxicas CD8-positivas e de células NK observados neste estudo, são descritas alterações funcionais destas células, levando a um estado de imunossupressão por comprometimento da resposta imune inata (Manfrere et al, 2017;Torrealba et al, 2017). Já o aumento da expressão de CD25 nos pacientes com SS pode ser devido ao aumento de células T reguladoras, o que podem contribuir para o efeito supressivo na resposta imune destes pacientes (Heid et al, 2009).…”