NKG2A gene variant predicts outcome of immunotherapy in AML and modulates the repertoire and function of NK cells

• DOI: 10.1136/jitc-2023-007202
• Publication Date: 2023-08-30T16:06:52Z
• Authors: Brwa Ali Hussein; Linnea Kristenson; Silvia Pesce; Anne Wöhr; Yarong Tian; Alexander Hallner; Mats Brune; Kristoffer Hellst...; Ka-Wei Tang; Elin Bernson; Fredrik B Thorén
• Keywords: NKG2D; Granzyme; Interleukin-7 receptor; K562 cells

The natural killer (NK) complex (NKC) harbors multiple genes such as KLRC1 (encoding NKG2A) and KLRK1 NKG2D) that are central to regulation of NK cell function. We aimed at determining what extent NKC haplotypes impact on repertoire function, whether gene variants outcome IL-2-based immunotherapy in acute myeloid leukemia (AML).Genotype status NKG2D rs1049174 NKG2A rs1983526 was determined using the TaqMan-Allelic discrimination approach. To dissect single nucloetide polymorphim (SNP) we engineered K562 line with CRISPR be killed a highly NKG2D-dependent fashion. cells were assayed for degranulation, intracellular cytokine production cytotoxicity flow cytometry.In AML patients receiving immunotherapy, variant, rs1983526, associated superior leukemia-free survival overall survival. observed degranulation from individuals high-cytotoxicity variant explained by presence larger, responsive NKG2A+ subset. Notably, donors homozygous favorable allele encoding mounted stronger responses when challenged leukemic cells, this genotype displayed higher accumulation granzyme B during histamine dihydrochloride/IL-2 immunotherapy. Additionally, among patients, SNP defined subset HLA-B-21 TT strikingly outcome.The study results imply dimorphism is enhanced effector function improved AML.