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.

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Journal
Blood Advances
Published
2026-04-17
DOI
https://doi.org/10.1182/bloodadvances.2025019066
Primary Topic
Immune Cell Function and Interaction
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article
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article

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

Takuya Yamamoto, Yuta Katayama, Yuta Hasegawa, Yuichi Inadomi⋆ et al.
Blood Advances
Immune Cell Function and Interaction
article

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

Takuya Yamamoto, Yuta Katayama, Yuta Hasegawa, Yuichi Inadomi⋆, Satoko Morishima, Akifumi Takaori‐Kondo, Akihito Yonezawa, Noriko Doki, Mizuki Watanabe, Kazunori Imada, Nobuaki Nakano, Fumihiko Matsuda, Tatsuo Ichinohe, Yoshiko Atsuta, Shuji Kawaguchi, Hidenori Tanaka, Masakazu Shimizu, Kentaro Serizawa, Junya Kanda, Makoto Onizuka, Makoto Yoshimitsu, Takero Shindo, Mari Morita‐Fujita, Taro Tsujimura, Yasuhiko Miyazaki, Yasuo Morishima, Kiyotaka Izumi, Masayasu Hayashi, Shoko Tarumoto, Meiko Takahashi, Takahiro Fukuda, Koji Kato, Yusuke Higuchi, Youko Suehiro
article en

Abstract

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.

Blood Advances
Kagoshima University (JP), Hiroshima University (JP), Tokai University (JP), Kyushu University (JP), Kyoto University (JP), Japanese Red Cross Hiroshima College of Nursing (JP), Tokyo Metropolitan Komagome Hospital (JP), National Hospital Organization Kyushu Cancer Center (JP), Hamanomachi Hospital (JP), Health Research Foundation (CA), Kindai University Sakai Hospital (JP), Oita Prefectural Hospital (JP), Osaka Hospital (JP), Hokkaido University Hospital (JP), National Institute of Technology, Miyakonojo College (JP), Kyoto University Hospital (JP), Tokyo National Hospital (JP), Kokura Memorial Hospital (JP), Kumamoto Medical Center (JP)
Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 21%
Immune Cell Function and Interaction
DOIOpen Access PDFOpenAlex
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