NKG2A blockade to unleash NK cells after haploidentical hematopoietic stem cell transplantation

Haploidentical Hematopoietic Stem Cell Transplantation (h-HSCT) is the only curative option for patients affected by hematologic malignancies, which allows to easily find a donor for most of patients in need. H-HSCT outcome is influenced by the quality of Immune Reconstitution (IR) early after transplant. In this setting, Natural Killer (NK) cells are the first lymphocytes to IR, thus providing a first line of protection and beneficial effects towards residual malignant cells. However, IR NK cells are poorly differentiated and display high levels of NKG2A, an inhibitory receptor also reported as a checkpoint inhibitor in several solid neoplasms. NKG2Ahigh NK cells display reduced cytotoxic features, being thus uncapable of clearing targets in vitro and bare diminished degranulation capacities. Based on this evidence, we set up a phase II clinical trial by administering to h-HSCT patients Monalizumab, a humanized anti-NKG2A monoclonal antibody, to unleash NK cell cytotoxic potential and ameliorate their recovery. Herein, we are investigating the effect of the NKG2A in vivo blockade on the phenotype and functions of IR NK cells. The results obtained showed that although Monalizumab doesn’t alter the kinetics of NK cell IR, it delays NK cell education, favouring NKG2A maintenance. Of note, NKG2Ahigh NK cells regained their degranulation capacity upon in vitro co-culture with K562-E cells, hinting that NKG2A blockade could possibly restore NK cell potential also in vivo.