Malignant hematopoietic cells expressing NK-activating and reduced HLA class I ligands

This target refers to a specific cellular phenotype observed in hematologic malignancies, such as acute myeloid leukemia (AML), where cancer cells downregulate Human Leukocyte Antigen (HLA) class I molecules to evade T-cell detection. This downregulation, combined with the expression of stress-induced ligands like MICA, MICB, and ULBPs, makes these cells primary targets for Natural Killer (NK) cells (Glycostem Therapeutics, 2024). NK cells utilize a balance of inhibitory and activating signals to identify these 'missing self' targets; the lack of HLA-I prevents inhibitory signaling through Killer-cell Immunoglobulin-like Receptors (KIRs), while the presence of activating ligands triggers receptors like NKG2D (Sutherland et al., 2002; DOI: 10.1182/blood-2002-03-0939). Therapeutic interventions, such as the adoptive transfer of ex vivo expanded allogeneic NK cells (e.g., oNKord), are designed to exploit this vulnerability to induce tumor cell lysis. This approach is particularly effective in patients with minimal residual disease or those ineligible for intensive chemotherapy. By bypassing the need for specific antigen recognition required by T-cells, NK cell therapies targeting this phenotype offer a broader application across various HLA-deficient hematologic cancers.

Other names

NK-sensitive malignant hematopoietic cellsHLA-I deficient cancer cellsNKG2D-ligand positive hematopoietic cellsMissing-self malignant cells

Natural Killer (NK) cells recognize these cells via the 'missing self' hypothesis, where the absence or reduction of HLA class I molecules fails to trigger inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs), and the 'induced self' model, where stress-induced ligands (e.g., MICA, MICB, ULBPs) trigger activating receptors like NKG2D (Ljunggren & Karre, 1990; DOI: 10.1038/346276a0; Sutherland et al., 2002; DOI: 10.1182/blood-2002-03-0939).