Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

Abstract

Background: In this study, the expression pattern of NKp30 and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3), as candidates for activating and inhibitory receptors of NK cells, were evaluated in patients with chronic lymphocytic leukemia (CLL). Patients and Methods: 24 CLL patients and 19 healthy controls were enrolled. Fresh peripheral blood was collected from all subjects and stained with fluorochrome-conjugated antibodies. The frequency of CD56+/CD3–/NKp30+ and CD56+/CD3–/Tim-3+ cells was determined by multicolor flow cytometry. Results: Our results revealed that Tim-3 is significantly upregulated on natural killer (NK) cells of CLL patients in comparison to healthy controls. NK cells of CLL patients showed lower expression of NKp30-activating receptor compared to controls. Tim-3 expression pattern on NK cells of CLL patients was correlated with poor prognostic factors including low hemoglobin level, high absolute lymphocyte count, and high serum C-reactive protein level. Conclusion: Dysregulated expression of Tim-3 and NKp30 receptors confirms the exhaustion state of NK cells in CLL. Our data introduce Tim-3 as a promising biomarker and potential target for immunotherapy of CLL.

Expression Analysis of Fyn and Bat3 Signal Transduction Molecules in Patients with Chronic Lymphocytic Leukemia

“…It has been demonstrated that Tim-3 is over-expressed on T-cells of several solid and hematological malignancies (Sakuishi et al, 2010;Riches et al, 2013;Hadadi et al, 2019). In agreement to this finding, our recent studies displayed more expression of Tim-3 and PD-1 on both CD4+ and CD8+ T cells from patients with CLL (Allahmoradi et al, 2017;Taghiloo et al, 2017).…”

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Most studies report that NK-cell number is increased in the peripheral blood of CLL patients and associates with better prognosis (27)(28)(29)(30)(31)(32)(33)(34). NK cells represent an appealing lymphocyte subset to be exploited in the context of immunotherapy, especially for their non-major histocompatibility complex (MHC)-restricted cytotoxicity (35).…”

Targeted Therapies: Friends or Foes for Patient’s NK Cell-Mediated Tumor Immune-Surveillance?

“…Other markers such as CD96, expressed by a subset of NK cells, or CD200, expressed on AML, may suppress patients NK cell functions [69,70]. Similarly, increased proportions of NKp30 low TIM-3 + NK cells were found in the PB of CLL patients [71] Moreover, leukemic blasts may release various soluble molecules, including soluble ligands of activating NK receptors, soluble factors, such as TGF-β or IL-10, reactive oxygen species (ROS), or express high levels of indoeamine-2,3-dioxygenase (IDO) and tryptophan catabolites, which inhibit NK cell functions and modulate NK cell receptors expression [72][73][74][75][76]. In AML patients' serum the presence of soluble NKG2D-L (MICA, MICB and ULBP2) is associated with a down-regulation of the surface NKG2D expression leading to an impairment in NKG2D-mediated NK-cell activity [77].…”