Long-read KIR genotyping reveals donor KIR/HLA polymorphisms linked to posttransplant relapse in T-cell malignancies

Donor polymorphisms in killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) shapes natural killer (NK) cell activity, which may influence relapse risk after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, comprehensive association studies have been limited by insufficient allele-level genotyping across KIR genes owing to their high sequence homology. Using high-resolution long-read genotyping of 15 KIR genes, we performed an unbiased discovery analysis in 219 allo-HSCTs for adult T-cell leukemia/lymphoma (ATL) to identify relapse-associated donor KIR/HLA polymorphisms. We tested associations for donor KIR/HLA amino acid-level combinations, accounting for linkage disequilibrium across KIR haplotypes. In addition, we validated the findings in independent cohorts. In ATL, KIR3DL1*005 or KIR3DS1*013 with glutamic acid at position 62 in the HLA-B α2 domain (HLA-B-D2-62E), or KIR3DL1*001/*007/015/*020 with HLA-B-D2-62V (valine) were identified as high-risk (H) combinations. Meanwhile, KIR3DL1*015 with isoleucine at position 80 in the HLA-B α1 domain (HLA-B-D1-80I), or KIR3DL1*001/*005/*007/*020 with HLA-B-D1-80T (threonine) were identified as low-risk (L) combinations. Compared with L−/H+ donors (N=119), L+/H−, L−/H−, and L+/H+ donors (N=80) showed reduced relapse (adjusted HR=0.36, 95% CI=0.19-0.65, P=7.5×10⁻⁴) and improved overall survival (adjusted HR=0.67, 95% CI=0.45-0.98, P=0.038). Those donors were also associated with reduced relapse in other T-cell malignancies (N=145, adjusted HR=0.37, 95% CI=0.16-0.89, P=0.026), but not in acute myeloid leukemia (N=965, P=0.77), suggesting disease specificity. Notably, low-risk combinations increased CD107a degranulation by KIR3DL1+ NK cells against HLA class I-deficient targets in vitro, consistent with enhanced NK-cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.