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 HLA shape natural killer (NK) cell activity, which may influence relapse risk after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, association studies have been limited by insufficient allele-level KIR genotyping. Using high-resolution, long-read genotyping of 15 KIR genes, we performed an unbiased discovery analysis in 219 patients with T-cell leukemia/lymphoma (ATL) who underwent allo-HSCT to identify relapse-associated donor KIR/HLA polymorphisms. We comprehensively tested associations between donor KIR/HLA amino acid-level combinations and relapse risk, accounting for linkage disequilibrium across KIR haplotypes, and 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) and KIR3DL1∗001/∗007/∗015/∗020 with HLA-B-D2-62V (valine) were high-risk (H) combinations. Meanwhile, KIR3DL1∗015 with isoleucine at position 80 in the HLA-B α1 domain (HLA-B-D1-80I) and KIR3DL1∗001/∗005/∗007/∗020 with HLA-B-D1-80T (threonine) were 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 hazard ratio [HR], 0.36; 95% confidence interval [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 = .038). Those donors were associated with reduced relapse in other T-cell malignancies (n = 145; adjusted HR, 0.37; 95% CI, 0.16-0.89; P = .026) but not in acute myeloid leukemia (n = 965; P = .77), suggesting disease specificity. Low-risk combinations increased CD107a degranulation of KIR3DL1+ NK cells against HLA class I-deficient targets, consistent with enhanced NK cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.