CD150 and CD180 are negative regulators of IL-10 expression and secretion in chronic lymphocytic leukemia B cells

Abstract

Chronic lymphocytic leukemia (CLL) is a strikingly heterogeneous disease both at the molecular level and clinical disease course. The key proliferation and survival signals malignant B cells obtain within lymph nodes or bone marrow. Moreover, CLL B cells and tumor microenvironment dynamically co-evolve organizing inflammatory and immunosuppressive microenvironment by direct contact with surrounding cells and secretion of cytokines, growth factors, or extracellular vesicles. Finding a way to weaken obtaining by malignant B cells supportive signals may improve CLL outcome and optimize treatment strategies. The aim of this study was to evaluate whether CD150 and CD180 cell surface receptors could be involved in the regulation of CLL B cellsderived cytokines (CCL3, CCL4, IL-6, and IL-10). The study was performed on malignant B cells isolated from peripheral blood of primary CLL patients. Flow cytometry, qPCR, ELISA, western blot, ex vivo cell surface ligation assay, ex vivo drug sensitivity assay, and cell viability assay were used in this study. The CCL3, CCL4, IL-6, and IL-10 mRNA expression levels were heterogeneously presented among studied CLL cases. The elevated CCL3/CCL4 and decreased IL-6/IL-10 expression level are specific features of CLL B cells with positive CD150 and CD180 expression status. Ligation of CD150 and CD180 receptors did not affect CCL3/CCL4 mRNA expression level in CLL B cells, while IL-6 and IL-10 were significantly decreased. After malignant B cells stimulation via CD150 and CD180 observed reduced IL-10 but not IL-6 level in culture supernatants. Ligation of CD150 and CD180 was linked to the classical NFregulation of phosphorylation level of NF-tions between basal mRNA expression levels of CLL3, CCL4, IL-6, and IL-10 in CLL B cells and their sensitivity to chemotherapeutic drugs ex vivo. High CCL3/CCL4 and low IL-10 mRNA expression levels are associated with malignant B cells` sensitivity to BEN, while high IL-6 levels are a sign of CLL B cells` resistance to FC. The revealed involvement of CD150 and CD180 in cytokine regulation expands our knowledge of the role of CD150 and CD180 in the pathobiology of CLL and their contribution to a favorable clinical outcome. Determining the cytokines expression levels together with CD150 and CD180 expression status may help to predict the responsiveness of CLL B cells to chemotherapeutic drugs and optimize personalized chemotherapy scheme.

Signaling Lymphocytic Activation Molecule Family Member 1 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication

“…NLR receptor genes recognize pathogenic microorganisms that invade the cell and regulate the innate immune response of the body against pathogenic microorganisms [ 41 ]. SLAMF1 genes act as negative regulators of type I interferon production and NF-κB activation, and SLAMF1 genes knockout mice showed reduced clearance of Gram-negative bacteria [ 42 ], indicating that the SLAMF1 gene has a very important role in immune regulation and disease prevention and control. In this study, we examined the expression of PRRs and cytokines in the cellular inflammatory pathway after SLAMF1 inhibited PRRSV replication and revealed that SLAMF1 could exert antiviral effects and suppress the level of virus-induced inflammation in Marc-145 cells.…”

SLAM Modification as an Immune-Modulatory Therapeutic Approach in Cancer

“…One such notable receptor, SLAMF1, serves as a suppressor of IL-10 expression and release on the B-CLL cell surface. There is a documented correlation between SLAMF1's presence and improved clinical prognosis in CLL patients [26]. Notably, an increased expression of both SLAMF1 and SLAMF7 emerges as a positive prognostic sign.…”

SLAM-family receptors come of age as a potential molecular target in cancer immunotherapy

“…Several studies have expanded current knowledge on SLAMF1 in the pathophysiology of CLL and lymphoma (12,85,87,(118)(119)(120). A study has demonstrated that SLAMF1 acts as a negative regulator of IL-10 expression and secretion on the surface of B cell CLL and is associated with favorable clinical outcomes (12).…”

“…Previous studies have reported the role of SLAMs in tumor immunity in a variety of cancers, including chronic lymphocytic leukemia (CLL) (11), lymphoma (12), multiple myeloma (MM) (13), acute myeloid leukemia (AML) (14), hepatocellular carcinoma (HCC) (15), head and neck squamous cell carcinoma (HNSCC) (16), pancreas (17), lung (17), and melanoma (18). Anti-CTLA-4 and anti-PD-1 mAbs have been incredibly effective.…”