Improvement of NK Cell Cytotoxicity in Reconstituting NK Cells after Allogeneic Stem Cell Transplantation by Blocking NKG۲A Checkpoint

Background: One cause of tumor relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the alteration of the graft-versus-tumor effect of early reconstituting natural killer (NK) cells due to overexpression of the NKG۲A inhibitory receptor. This study aims to determine the effect of Monalizumab, an anti- NKG۲A receptor, on the effector functions of reconstituting NK cells after allo-HSCT.Method: In this prospective cohort study, ۱۸ patients with hematological malignancies were divided into three groups: dose ۱ group (۰.۱ mg/kg, n = ۵), dose ۲ group (۰.۵ mg/kg, n = ۸), and dose ۳ group (۱ mg/kg, n = ۵), and followed up for six months. Blood samples were taken directly before the administration of Monalizumab and at different time points post-treatment. Reconstituting NK cells were phenotypically and functionally assessed by flow cytometry.Results: Our results showed a more pronounced increase in the expression of activating NK receptors (NKG۲D, NKp۳۰, NKp۴۶) on the reconstituting CD۵۶dim NK cells of patients receiving ۱ mg/kg of Monalizumab compared with other participants. Additionally, we observed that patients treated with dose ۳ of Monalizumab had the highest levels of degranulation compared with other patients and controls. Moreover, we noticed that CD۵۶dim NK cells of dose ۲- and dose ۳-related patients produced significant levels of perforin, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) in response to K۵۶۲ stimulation post-Monalizumab treatment compared with controls and dose ۱-treated patients.Conclusion: We suggest that using Monalizumab improves the phenotype and cytotoxicity of reconstituting NK cells after allo-HSCT.

Keywords:

Natural Killer Cells , Monalizumab , NKG۲A , Cell cytotoxicity , Allogeneic hematopoietic stem cell transplantation