Faculty Collaboration Database

Impact of the HLA Immunopeptidome on Survival of Leukemia Patients After Unrelated Donor Transplantation. J Clin Oncol 2023 May 01;41(13):2416-2427

Date

01/21/2023

Pubmed ID

36669145

Pubmed Central ID

PMC10150892

DOI

10.1200/JCO.22.01229

Scopus ID

2-s2.0-85159250781 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

PURPOSE: Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we tested this concept in HLA-A, -B, and -C disparities after single class I HLA-mismatched UD-HCT.

PATIENTS AND METHODS: We studied 2,391 single class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 for acute leukemia or myelodysplastic syndromes. Hierarchical clustering of experimentally determined peptide-binding motifs (PBM) was used as a proxy for immunopeptidome divergence of HLA-A, -B, or -C disparities, allowing us to classify 1,629/2,391 (68.1%) of the HLA-mismatched UD-HCT as PBM-matched or PBM-mismatched. Risks associated with PBM-matching status were assessed by Cox proportional hazards models, with overall survival (OS) as the primary end point.

RESULTS: Relative to full matches, bidirectional or unidirectional PBM mismatches in graft-versus-host (GVH) direction (PBM-GVH mismatches, 60.7%) were associated with significantly lower OS (hazard ratio [HR], 1.48; P < .0001), while unidirectional PBM mismatches in host-versus-graft direction or PBM matches (PBM-GVH matches, 39.3%) were not (HR, 1.13; P = .1017). PBM-GVH mismatches also had significantly lower OS than PBM-GVH matches in direct comparison (HR, 1.32; P = .0036). The hazards for transplant-related mortality and acute and chronic graft-versus-host disease but not relapse increased stepwise from full HLA matches to single PBM-GVH matches, and single PBM-GVH mismatches. A webtool for PBM-matching of single class I HLA-mismatched donor-recipient pairs was developed.

CONCLUSION: PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome. These findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.

Author List

Crivello P, Arrieta-Bolaños E, He M, Wang T, Fingerson S, Gadalla SM, Paczesny S, Marsh SGE, Lee SJ, Spellman SR, Bolon YT, Fleischhauer K

Author

Tao Wang PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Graft vs Host Disease
HLA Antigens
HLA-A Antigens
Hematopoietic Stem Cell Transplantation
Histocompatibility Testing
Humans
Leukemia, Myeloid, Acute
Prospective Studies
Retrospective Studies
Unrelated Donors