Characterization of stem cells in acute myeloid leukemia - The role of human leukocyte antigens for immune suppression in normal and aberrant karyotype

Abstract

Relapse remains a major cause of mortality in acute myeloid leukemia (AML), highlighting the need for effective remission maintenance therapies. Combination immunotherapy with histamine dihydrochloride (HDC) and interleukin-2 (IL-2) is approved in the European Union as a natural killer (NK) cell-stimulating treatment for relapse prevention in AML. Results from a phase IV trial of HDC/IL-2 suggest that its clinical benefit is more pronounced in patients with normal karyotype AML than those with chromosomal aberrations. This project aimed to characterize immunogenic features of stem and progenitor cells in newly diagnosed AML patients and to determine whether mechanisms of NK cell immune evasion are more prevalent in aberrant than normal karyotype AML. Single-cell sequencing data from 31 patients with newly diagnosed AML (normal karyotype, n = 12; aberrant karyotype, n = 19) and 5 healthy donors were analyzed to assess differences in cell proportions, expression of natural killer (NK) cell inhibitory ligands with a focus on human leukocyte antigen (HLA)-A,-B,-C, and-E, gene set enrichment, and inferred cell-cell signaling. To complement to the bioinformatic analyses, flow cytometry was performed on mononuclear cells from newly diagnosed AML patient samples (n=10) to evaluate cell-type composition and HLA expression. Expression of inhibitory ligands, including HLA-ABC and HLA-E, was elevated in aberrant karyotype AML. Enrichment of interferon response gene signatures in this subgroup suggested increased interferon exposure or signaling as a potential driver of HLA upregulation. Comparative cell-cell signaling analyses revealed enhanced HLA-E-mediated regulatory signaling toward NK cells, as well as increased HLA ABC-dependent antigen presenting interactions with cytotoxic T lymphocytes in aberrant karyotype AML. Further studies are needed to define the functional con sequences of these signaling interactions and to further characterize the complex immune landscape of AML.