Faculty Collaboration Database

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT. Blood Adv 2023 May 09;7(9):1635-1649

Date

12/09/2022

Pubmed ID

36477467

Pubmed Central ID

PMC10182302

DOI

10.1182/bloodadvances.2022008863

Scopus ID

2-s2.0-85163424373 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

T-cell responses to minor histocompatibility antigens (mHAs) mediate graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation. Therapies that boost T-cell responses improve allogeneic hematopoietic cell transplant (alloHCT) efficacy but are limited by concurrent increases in the incidence and severity of GVHD. mHAs with expression restricted to hematopoietic tissue (GVL mHAs) are attractive targets for driving GVL without causing GVHD. Prior work to identify mHAs has focused on a small set of mHAs or population-level single-nucleotide polymorphism-association studies. We report the discovery of a large set of novel GVL mHAs based on predicted immunogenicity, tissue expression, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT data set of 3231 alloHCT DRPs. The total number of predicted mHAs varied by HLA allele, and the total number and number of each class of mHA significantly differed by recipient genomic ancestry group. From the pool of predicted mHAs, we identified the smallest sets of GVL mHAs needed to cover 100% of DRPs with a given HLA allele. We used mass spectrometry to search for high-population frequency mHAs for 3 common HLA alleles. We validated 24 predicted novel GVL mHAs that are found cumulatively within 98.8%, 60.7%, and 78.9% of DRPs within DISCOVeRY-BMT that express HLA-A∗02:01, HLA-B∗35:01, and HLA-C∗07:02, respectively. We confirmed the immunogenicity of an example novel mHA via T-cell coculture with peptide-pulsed dendritic cells. This work demonstrates that the identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics.

Author List

Olsen KS, Jadi O, Dexheimer S, Bortone DS, Vensko SP, Bennett S, Tang H, Diiorio M, Saran T, Dingfelder D, Zhu Q, Wang Y, Haiman CA, Pooler L, Sheng X, Webb A, Pasquini MC, McCarthy PL, Spellman SR, Weimer E, Hahn T, Sucheston-Campbell L, Armistead PM, Vincent BG

Author

Marcelo C. Pasquini MD, MS Professor in the Medicine department at Medical College of Wisconsin

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

Adolescent
Adult
Dendritic Cells
Female
Graft vs Host Disease
HLA Antigens
Hematopoietic Stem Cell Transplantation
Humans
Leukemia
Male
Middle Aged
Minor Histocompatibility Antigens
T-Lymphocytes
Transplantation, Homologous
Young Adult