title: Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia.
abstract: Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored thein vitropreclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients. Our work confirmed overexpression of HLA-E on CLL B-cells and demonstrated NKG2A expression on CD56+/16+ NK-cells from CLL patients. We also demonstrate that blocking NKG2A on CLL NK-cells was sufficient to restore direct cytotoxicity ability of NK-cells against HLA-E-expressing targets without impacting NK-cell mediated antibody-dependent cellular cytotoxicity. Additionally, we proved the specificity of monalizumab in blocking NKG2A through Fc-blocking mechanisms. This paper provides justification for the potential clinical utility of monalizumab in the treatment of patients with CLL.
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: McWilliams
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mele
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Timmerman
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Faraz
authors.initials: F
authors.lastname: Fiazuddin
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Strattan
authors.affiliation: Center for Biostatistics, The Ohio State University , Columbus, OH, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA.
authors.forename: Farrukh T
authors.initials: FT
authors.lastname: Awan
keywords: Chronic lymphocytic leukemia; natural killer cells