Cell Avidity Uncovers Novel KIR:HLA binding predicting patient survival post stem cell transplant

Despite significant progress in haploidentical hematopoietic cell transplantation (haploHCT) for leukemia, relapse-free survival remains a major challenge, even with the addition of immune effectors such as NK or T cells. Given the crucial role of NK cells and their killer immunoglobulin receptors (KIRs) in early anti-leukemic activity, this study sought to refine the understanding of KIR:HLA (human leukocyte antigen) interactions in order to better predict patient outcomes.Using a combination of in silico protein folding and interaction modeling with in vitro acoustic force microscopy to quantify cell avidity, Peter's group identified and validated a novel functional interaction between full-length KIR2DS4 and HLA-B*35. This interaction was confirmed through cell avidity assays with monoallelic KIR and HLA cell lines. When applied to clinical data, patients who received haploHCT and NK cell addback from donors expressing only full-length KIR2DS4 showed significantly improved overall and relapse-free survival. These findings were independently validated in an adult cohort, revealing consistent survival advantages.This newly defined KIR2DS4:HLA-B*35 axis represents an immediately actionable marker for donor selection and offers a mechanistic insight into optimizing NK cell-mediated anti-leukemic responses.