Immunogenetic Harmony and Discord: The Expanding Role of Killer Cell Immunoglobulin-like Receptors (KIR) in Hematopoietic Stem Cell Transplantation (HSCT) Outcomes
DOI:
https://doi.org/10.62382/j1mjwv45Keywords:
KIR-HLA interactions, natural killer cell licensing, hematopoietic stem cell transplantation, graft-versus-host disease, bioinformatics, CAR-NK therapyAbstract
Killer cell immunoglobulin-like receptors (KIRs) that regulate the activity of the natural killer (NK) cells are determinants of immune response during hematopoietic stem cell transplantation (HSCT). They interact with, and thus modulate alloreactivity, graft success, and post-transplant immune surveillance with human leukocyte antigen (HLA) class I molecules. Recently, an increased interest has been generated in exploiting KIR-HLA interactions to enhance the success of transplantation. It has given us an opportunity for a critical, in-depth review of the KIRs' biological functionality, the diversity, and clinical significance in HSCT among various populations across the world. This review evaluates the outcomes of graft-versus-host disease (GVHD), relapse, risk of infections, and survival with respect to KIR genotype matching, ligand recognition, and licensing. Evidence suggests that donor KIR B haplotypes and KIR-ligand mismatching can optimize graft-versus-leukemia (GVL) effects without increasing GVHD in certain HSCT settings. In the future, integration of KIR-HLA mismatching for donor selection will be essential for achieving the best results for HSCT.
References
[1]Dalle J-H, de Latour RP. Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. International Journal of Hematology, 2016, 103(4), 373-379. DOI: 10.1007/s12185-016-1951-0
[2]Yanir A, Schulz A, Lawitschka A, Nierkens S, Eyrich M. Immune reconstitution after allogeneic haematopoietic cell transplantation: From observational studies to targeted interventions. Frontiers in Pediatrics, 2022, 9, 786017. DOI: 10.3389/fped.2021.786017
[3]Downing J, D’Orsogna L. High-resolution human KIR genotyping. Immunogenetics, 2022, 74(4), 369-379. DOI: 10.1007/s00251-021-01247-0
[4]Augusto DG, Norman PJ, Dandekar R, Hollenbach JA. Fluctuating and geographically specific selection characterize rapid evolution of the human KIR region. Frontiers in Immunology, 2019, 10, 989. DOI: 10.3389/fimmu.2019.00989
[5]de Groot NG, Blokhuis JH, Otting N, Doxiadis GG, Bontrop RE. Co‐evolution of the MHC class I and KIR gene families in rhesus macaques: Ancestry and plasticity. Immunological Reviews, 2015, 267(1), 228-245. DOI: 10.1111/imr.12313
[6]Deborska-Materkowska D, Perkowska-Ptasinska A, Sadowska-Jakubowicz A, Gozdowska J, Ciszek M, Pazik J, et al. Killer immunoglobulin-like receptor 2DS2 (KIR2DS2), KIR2DL2-HLA-C1, and KIR2DL3 as genetic markers for stratifying the risk of cytomegalovirus infection in kidney transplant recipients. International Journal of Molecular Sciences, 2019, 20(3), 546. DOI: 10.3390/ijms20030546
[7]Cisneros E, Moraru M, Gómez-Lozano N, Muntasell A, López-Botet M, Vilches C. Haplotype-based analysis of KIR-gene profiles in a south european population—distribution of standard and variant haplotypes, and identification of novel recombinant structures. Frontiers in Immunology, 2020, 11, 440. DOI: 10.3389/fimmu.2020.00440
[8]Körner C, Altfeld M. Role of KIR3DS1 in human diseases. Frontiers in Immunology, 2012, 3, 326. DOI: 10.3389/fimmu.2012.00326
[9]Long EO. Negative signaling by inhibitory receptors: The NK cell paradigm. Immunological Reviews, 2008, 224(1), 70-84. DOI: 10.1111/j.1600-065X.2008.00660.x
[10]Dębska-Zielkowska J, Moszkowska G, Zieliński M, Zielińska H, Dukat-Mazurek A, Trzonkowski P, et al. KIR receptors as key regulators of NK cells activity in health and disease. Cells, 2021, 10(7), 1777. DOI: 10.3390/cells10071777
[11]Bernson E. Impact of NK cell repertoires on immunotherapy in acute myelod leukemia. University of Gothenburg, 2017.
[12]Agnello L, Masucci A, Tamburello M, Vassallo R. The role of killer Ig-like receptors in diseases from A to Z. International Journal of Molecular Sciences, 2025, 26(7), 3242. DOI:10.3390/ijms26073242
[13]Bakhtiari T, Ahmadvand M, Salmaninejad A, Ghaderi A, Yaghmaie M, Sadeghi A, et al. The influence of KIR gene polymorphisms and KIR-ligand binding on outcomes in hematologic malignancies following haploidentical stem cell transplantation: A comprehensive review. Current Cancer Drug Targets, 2023, 23(11), 868-878. DOI: 10.2174/1568009623666230523155808
[14]Baumeister SH, Rambaldi B, Shapiro RM, Romee R. Key aspects of the immunobiology of haploidentical hematopoietic cell transplantation. Frontiers in Immunology, 2020, 11, 191. DOI: 10.3389/fimmu.2020.00191
[15]Mancusi A, Ruggeri L, Urbani E, Pierini A, Massei MS, Carotti A, et al. Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRS reduces nonrelapse mortality. Blood, 2015, 125(20), 3173-3182. DOI: 10.1182/blood-2014-09-599993
[16]Gao F, Ye Y, Gao Y, Huang H, Zhao Y. Influence of KIR and NK cell reconstitution in the outcomes of hematopoietic stem cell transplantation. Frontiers in Immunology, 2020, 11, 2022. DOI: 10.3389/fimmu.2020.02022
[17]Cao Y, Wang X, Jin T, Tian Y, Dai C, Widarma C, et al. Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy. Signal Transduction and Targeted Therapy, 2020, 5(1), 250. DOI: 10.1038/s41392-020-00348-8
[18]Hò G-GT, Celik AA, Huyton T, Hiemisch W, Blasczyk R, Simper GS, et al. NKG2A/CD94 is a new immune receptor for HLA-G and distinguishes amino acid differences in the HLA-G heavy chain. International Journal of Molecular Sciences, 2020, 21(12), 4362. DOI: 10.3390/ijms21124362
[19]Borrok MJ, Luheshi NM, Beyaz N, Davies GC, Legg JW, Wu H, et al. Enhancement of antibody-dependent cell-mediated cytotoxicity by endowing IgG with FcαRI (CD89) binding. MAbs, 2015, 7(4), 743-751. DOI: 10.1080/19420862.2015.1047570
[20]Hecht M-L, Rosental B, Horlacher T, Hershkovitz O, De Paz JL, Noti C, et al. Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. Journal of Proteome Research, 2009, 8(2), 712-720. DOI: 10.1021/pr800747c
[21]Lozano E, Díaz T, Mena M-P, Suñe G, Calvo X, Calderón M, et al. Loss of the immune checkpoint CD85j/LILRB1 on malignant plasma cells contributes to immune escape in multiple myeloma. Journal of Immunology, 2018, 200(8), 2581-2591. DOI: 10.4049/jimmunol.1701622
[22]Cai L, Li Y, Tan J, Xu L, Li Y. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. Journal of Hematology & Oncology, 2023, 16(1), 101. DOI: 10.1186/s13045-023-01499-1
[23]Attalla K, Farkas AM, Anastos H, Audenet F, Galsky MD, Bhardwaj N, et al. TIM-3 and TIGIT are possible immune checkpoint targets in patients with bladder cancer. Urologic Oncology: Seminars and Original Investigations, 2022, 40(9), 403-406. DOI: 10.1016/j.urolonc.2020.06.007
[24]Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: Dynamics and clinical implications. Blood, 2018, 131(2), 247-262. DOI: 10.1182/blood-2017-05-780668
[25]Schenk A, Bloch W, Zimmer P. Natural killer cells—an epigenetic perspective of development and regulation. International Journal of Molecular Sciences, 2016, 17(3), 326. DOI: 10.3390/ijms17030326
[26]Trowsdale J, Jones DC, Barrow AD, Traherne JA. Surveillance of cell and tissue perturbation by receptors in the LRC. Immunological Reviews, 2015, 267(1), 117-136. DOI: 10.1111/imr.12314
[27]Xia M, Wang B, Wang Z, Zhang X, Wang X. Epigenetic regulation of NK cell-mediated antitumor immunity. Frontiers in Immunology, 2021, 12, 672328. DOI: 10.3389/fimmu.2021.672328
[28]Ji Y, Xiao C, Fan T, Deng Z, Wang D, Cai W, et al. The epigenetic hallmarks of immune cells in cancer. Molecular Cancer, 2025, 24(1), 66. DOI: 10.1186/s12943-025-02255-4
[29]Zhi Y, Li M, Lv G. Into the multi-omics era: Progress of t cells profiling in the context of solid organ transplantation. Frontiers in Immunology, 2023, 14, 1058296. DOI: 10.3389/fimmu.2023.1058296
[30]Sevcikova A, Fridrichova I, Nikolaieva N, Kalinkova L, Omelka R, Martiniakova M, et al. Clinical significance of microRNAs in hematologic malignancies and hematopoietic stem cell transplantation. Cancers, 2023, 15(9), 2658. DOI: 10.3390/cancers15092658
[31]Lau CM, Wiedemann GM, Sun JC. Epigenetic regulation of natural killer cell memory. Immunological Reviews, 2022, 305(1), 90-110. DOI: 10.1111/imr.13031
[32]Gragert L. Analysis of human leukocyte antigen (HLA) immunogenetic data for hematopoietic stem cell transplantation and disease association. University of Minnesota Twin Cities, 2014.
[33]Partanen J, Hyvärinen K, Bickeböller H, Bogunia-Kubik K, Crossland RE, Ivanova M, et al. Review of genetic variation as a predictive biomarker for chronic graft-versus-host-disease after allogeneic stem cell transplantation. Frontiers in Immunology, 2020, 11, 575492. DOI: 10.3389/fimmu.2020.575492
[34]Giaccone L, Faraci DG, Butera S, Lia G, Di Vito C, Gabrielli G, et al. Biomarkers for acute and chronic graft versus host disease: State of the art. Expert Review of Hematology, 2021, 14(1), 79-96. DOI: 10.1080/17474086.2021.1860001
[35]DÁrrigo C. The International Congress of Pathology & Laboratory Medicine 2023: Precision medicine: Revolutionizing pathology in genomic era, organised by the College of Pathologists, Academy of Medicine of Malaysia and at World Trade Centre Kuala Lumpur on 20-22 September 2023. Malaysian Journal of Pathology, 2023, 45(3), 481-566.
[36]Zhao J, Wang X, Zhu H, Wei S, Zhang H, Ma L, et al. Exploring natural killer cell-related biomarkers in multiple myeloma: A novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study. Clinical and Experimental Medicine, 2024, 24(1), 79. DOI: 10.1007/s10238-024-01322-2
[37]Lange V, Böhme I, Hofmann J, Lang K, Sauter J, Schöne B, et al. Cost-efficient high-throughput HLA typing by MiSeq amplicon sequencing. BMC Genomics, 2014, 15(1), 63. DOI: 10.1186/1471-2164-15-63
[38]Chhabra R. Molecular and modular intricacies of precision oncology. Frontiers in Immunology, 2024, 15, 1476494. DOI: 10.3389/fimmu.2024.1476494
[39]Geneugelijk K, Thus KA, van Deutekom HWM, Calis JJA, Borst E, Keşmir C, et al. Exploratory study of predicted indirectly recognizable HLA epitopes in mismatched hematopoietic cell transplantations. Frontiers in Immunology, 2019, 10, 880. DOI: 10.3389/fimmu.2019.00880
[40]Wiebe C, Nickerson P. Strategic use of epitope matching to improve outcomes. Transplantation, 2016, 100(10), 2048-2052. DOI: 10.1097/tp.0000000000001284
[41]Collin CB, Gebhardt T, Golebiewski M, Karaderi T, Hillemanns M, Khan FM, et al. Computational models for clinical applications in personalized medicine—guidelines and recommendations for data integration and model validation. Journal of Personalized Medicine, 2022, 12(2), 166. DOI: 10.3390/jpm12020166.
[42]Khosroabadi Z, Azaryar S, Dianat-Moghadam H, Amoozgar Z, Sharifi M. Single cell RNA sequencing improves the next generation of approaches to AML treatment: Challenges and perspectives. Molecular Medicine, 2025, 31(1), 33. DOI: 10.1186/s10020-025-01085-w
[43]Li W, Huang D, Luo Z, Zhou T, Jin Z. Yinchenhao decoction mitigates cholestatic liver injury in mice via gut microbiota regulation and activation of FXR-FGF15 pathway. Pharmaceuticals, 2025, 18(7), 932. DOI: 10.3390/ph18070932
[44]Norman Paul J, Hollenbach Jill A, Nemat-Gorgani N, Marin Wesley M, Norberg Steven J, Ashouri E, et al. Defining KIR and HLA class I genotypes at highest resolution via high-throughput sequencing. The American Journal of Human Genetics, 2016, 99(2), 375-391. DOI: 10.1016/j.ajhg.2016.06.023
[45]Wang J, Belosevic M, Stafford JL. Identification of distinct LRC- and Fc receptor complex-like chromosomal regions in fish supports that teleost leukocyte immune-type receptors are distant relatives of mammalian Fc receptor-like molecules. Immunogenetics, 2021, 73(1), 93-109. DOI: 10.1007/s00251-020-01193-3
[46]Kulkarni S, Martin MP, Carrington M. KIR genotyping by multiplex PCR-SSP. Methods in Molecular Biology, 2010, 612, 365-375. DOI: 10.1007/978-1-60761-362-6_25
[47]Schöfl G, Lang K, Quenzel P, Böhme I, Sauter J, Hofmann JA, et al. 2.7 million samples genotyped for HLA by next generation sequencing: Lessons learned. BMC Genomics, 2017, 18(1), 161. DOI: 10.1186/s12864-017-3575-z
[48]Oehler JB, Wright H, Stark Z, Mallett AJ, Schmitz U. The application of long-read sequencing in clinical settings. Human Genomics, 2023, 17(1), 73. DOI: 10.1186/s40246-023-00522-3
[49]Chen X, Gupta P, Wang J, Nakitandwe J, Roberts K, Dalton JD, et al. Conserting: Integrating copy-number analysis with structural-variation detection. Nature Methods, 2015, 12(6), 527-530. DOI: 10.1038/nmeth.3394
[50]Vukcevic D, Traherne James A, Næss S, Ellinghaus E, Kamatani Y, Dilthey A, et al. Imputation of KIR types from SNP variation data. The American Journal of Human Genetics, 2015, 97(4), 593-607. DOI: 10.1016/j.ajhg.2015.09.005
[51]Wagner I, Schefzyk D, Pruschke J, Schöfl G, Schöne B, Gruber N, et al. Allele-level KIR genotyping of more than a million samples: Workflow, algorithm, and observations. Frontiers in Immunology, 2018, 9:2843. DOI: 10.3389/fimmu.2018.02843
[52]Jiang W, Johnson C, Simecek N, López-Álvarez M, Di D, Trowsdale J, et al. qKAT: a high-throughput qPCR method for KIR gene copy number and haplotype determination. Genome Medicine, 2016, 8(1), 99. DOI: 10.1186/s13073-016-0358-0
[53]Qiao Y, Liu X, Harvard C, Nolin SL, Brown WT, Koochek M, et al. Large-scale copy number variants (CNVs): distribution in normal subjects and FISH/real-time qPCR analysis. BMC Genomics, 2007, 8(1), 167. DOI: 10.1186/1471-2164-8-167
[54]Cao H, Wang Y, Zhang W, Chai X, Zhang X, Chen S, et al. A short‐read multiplex sequencing method for reliable, cost‐effective and high‐throughput genotyping in large‐scale studies. Human Mutation, 2013, 34(12), 1715-1720. DOI: 10.1002/humu.22439
[55]Hung TK, Liu WC, Lai SK, Chuang HW, Lee YC, Lin HY, et al. Genetic diversity and structural complexity of the killer-cell immunoglobulin-like receptor gene complex: A comprehensive analysis using human pangenome assemblies. Genome Research. 2024, 34(8),1211-1223. DOI: 10.1101/gr.278358.123
[56]Newey PJ. Clinical genetic testing in endocrinology: Current concepts and contemporary challenges. Clinical Endocrinology, 2019, 91(5), 587-607. DOI: 10.1111/cen.14053
[57]Chen J, Madireddi S, Nagarkar D, Migdal M, Vander Heiden J, Chang D, et al. In silico tools for accurate HLA and KIR inference from clinical sequencing data empower immunogenetics on individual-patient and population scales. Briefings in Bioinformatics, 2021, 22(3). DOI: 10.1093/bib/bbaa223
[58]Karnes JH, Shaffer CM, Cronin R, Bastarache L, Gaudieri S, James I, et al. Influence of human leukocyte antigen (HLA) alleles and killer cell immunoglobulin‐like receptors (KIR) types on heparin‐induced thrombocytopenia (HIT). Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2017, 37(9), 1164-1171. DOI: 10.1002/phar.1983
[59]Urzì Brancati V, Scarpignato C, Minutoli L, Pallio G. Use of pharmacogenetics to optimize immunosuppressant therapy in kidney-transplanted patients. Biomedicines, 2022, 10(8), 1798. DOI: 10.3390/biomedicines10081798
[60]Robinson JI, Yusof MYM, Davies V, Wild D, Morgan M, Taylor JC, et al. Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity. EBioMedicine, 2022, 86. DOI: 10.1016/j.ebiom.2022.104343
[61]Selby PR, Shakib S, Peake SL, Warner MS, Yeung D, Hahn U, et al. A systematic review of the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of ganciclovir/valganciclovir in allogeneic haematopoietic stem cell transplant patients. Clinical Pharmacokinetics, 2021, 60(6), 727-739. DOI: 10.1007/s40262-020-00982-z
[62]Clubb JD, Gao TA, Chen YY. Synthetic biology in the engineering of CAR-T and CAR-NK cell therapies: Facts and hopes. Clinical Cancer Research, 2023, 29(8), 1390-1402. DOI: 10.1158/1078-0432.CCR-22-1491
[63]Jo DH. Innovative approaches to natural killer cell engineering: Overcoming challenges in CRISPR-Cas9 genome editing, transgene expression, and cryopreservation. University of Ottawa, 2025.
[64]Khan AB. Targeting therapeutic t cells to the bone marrow niche. University College London, 2019.
[65]Nowakowska P. Establishment of a good manufacturing practice-compliant procedure for expansion of therapeutic doses of genetically modified, CAR expressing NK-92 cells for the treatment of ErbB2-positive malignancies. der Technischen Universität Darmstadt, 2016.
[66]Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nature Reviews Cancer, 2022, 22(10), 557-575. DOI: 10.1038/s41568-022-00491-0
[67]Kundu S, Gurney M, O'Dwyer M. Generating natural killer cells for adoptive transfer: Expanding horizons. Cytotherapy, 2021, 23(7), 559-566. DOI: 10.1016/j.jcyt.2020.12.002
[68]Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: A report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biology of Blood and Marrow Transplantation, 2006, 12(8), 876-884. DOI: 10.1016/j.bbmt.2006.05.007
[69]Ng MS, Charu V, Johnson DW, O’Shaughnessy MM, Mallett AJ. National and international kidney failure registries: Characteristics, commonalities, and contrasts. Kidney International, 2022, 101(1), 23-35. DOI: 10.1016/j.kint.2021.09.024
[70]Cameron C, Fireman B, Hutton B, Clifford T, Coyle D, Wells G, et al. Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: Challenges and opportunities. Systematic Reviews, 2015, 4(1), 147. DOI: 10.1186/s13643-015-0133-0
[71]Alavinejad M, Shirzad M, Javid-Naderi MJ, Rahdar A, Fathi-Karkan S, Pandey S. Smart nanomedicines powered by artificial intelligence: A breakthrough in lung cancer diagnosis and treatment. Medical Oncology, 2025, 42(5), 134. DOI: 10.1007/s12032-025-02680-x
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Copyright (c) 2025 Imran Khan Yousafzai, Aqsa Mehreen, Nadia Noreen, Khadija Tariq, Rehan Ullah (Author)
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