Monalizumab-Mediated NKG2A Blockade Shapes Early NK Cell Function after Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical Hematopoietic Stem Cell Transplantation (h-HSCT) represents a curative option for patients affected by hematologic malignancies and ensures rapid donor availability for most recipients. Transplant outcomes are critically influenced by the quality of immune reconstitution (IR). In this context, Natural Killer (NK) cells are the first lymphocytes to reconstitute, providing immediate immune protection and contributing to graft-versus-leukemia effects. However, IR NK cells are poorly differentiated and characterized by high expression of the inhibitory receptor NKG2A, a checkpoint molecule associated with impaired cytotoxic function and reduced degranulation capacity in several malignancies. On this basis, we conducted a phase II clinical trial administering Monalizumab, a humanized anti-NKG2A monoclonal antibody, to h-HSCT recipients with the aim of enhancing NK cell functional recovery. By using this unique setting, we investigated the impact of in vivo NKG2A blockade on the phenotype and function of reconstituting NK cells. Our results demonstrate that Monalizumab does not affect the kinetics of NK cell reconstitution, but appears to delay NK cell education, promoting the persistence of an NKG2Ahigh phenotype. Despite this sustained NKG2A expression, reconstituting NK cells fully recovered their degranulation capacity following in vitro challenge with K562-E target cells. Collectively, our data support NKG2A blockade as a strategy to functionally reprogram early NK cell reconstitution after h‑HSCT, potentially enhancing beneficial early post‑transplant immune responses.