Fiche publication
Date publication
août 2026
Journal
Blood advances
Auteurs
Membres identifiés du Cancéropôle Est :
Pr PAGLIUCA Simona
Tous les auteurs :
Pagliuca S, Mooyaart JE, Ayuk FA, Zeiser R, Potter V, Dreger P, Bethge WA, Hilgendorf I, Michonneau D, Rambaldi A, Sengeloev H, Passweg JR, Richardson DS, Gedde-Dahl T, Kinsella FAM, Edinger M, Mielke S, Eder M, Andreani M, Crivello P, Merli P, Hoogenboom JD, de Wreede LC, Chabannon C, Kuball J, Gurnari C, Fleischhauer K, Ruggeri A, Lenz T
Lien Pubmed
Résumé
Allogeneic hematopoietic cell transplantation (allo-HCT) hinges on a delicate trade-off between graft-versus-tumor control and graft-versus-host disease (GvHD), mediated by donor T-cell recognition of antigens presented by recipient human leukocyte antigen (HLA) molecules. We hypothesized that, beyond allele-level matching, sequence divergence at peptide-binding grooves across donor and recipient HLA loci shapes these responses. To this end, we evaluated the effect of HLA evolutionary divergence (HED), a metric quantifying amino acid variability at HLA peptide-binding sites, on selected hematological malignancies in 4,695 patients undergoing allo-HCT from a 9/10 mismatched unrelated donor (MMUD), reported to the EBMT database. We examined (i) locus-specific recipient HED (HED-R) and (ii) "HED-mismatch" (HED-MM), capturing immunopeptidome divergence at the mismatched locus. While dichotomous mismatch status explained differences in survival and acute GvHD risk (with overall greater detriment for class I loci), HED metrics uncovered substantial within-mismatch heterogeneity. In DRB1 mismatched subgroup, HED-MM at this locus, independently predicted inferior relapse-free survival (RFS) with an attenuating time-dependent association, further modulated by cross-locus HED-R. In this subgroup, higher HED-R at HLA-A and HLA-C associated with increased risks of acute GvHD and non-relapse mortality, respectively. Among HLA-B-mismatched pairs, higher DRB1 HED-R associated with worse overall survival (OS) and RFS and higher relapse risk. In the HLA-A-mismatched subgroup, higher HED-R at HLA-A increased chronic GvHD risk. Collectively, HED-derived metrics complement conventional mismatch classification by capturing qualitative differences in donor-recipient immunopeptidome interactions and reveal a complex, non-linear interplay among alleles across mismatch subgroups that modulates the clinical impact of mismatching.
Référence
Blood Adv. 2026 08 25;:
