Year: 2022
Type: article
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.
Source: Blood Advances
Authors: Kelly S. Olsen, Othmane Jadi, Sarah Dexheimer, Dante S. Bortone, Steven P. Vensko, Sarah Bennett, Hancong Tang, Marisa Diiorio, Tanvi Saran, David Dingfelder, Qianqian Zhu, Yiwen Wang, Christopher A. Haiman, Loreall Pooler, Xin Sheng, Amy Webb, Marcelo C. Pasquini, Philip L. McCarthy, Stephen R. Spellman, Eric Weimer, Theresa Hahn, Lara Sucheston-Campbell, Paul M. Armistead, Benjamin G. Vincent
Institutions: University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, The Ohio State University, Roswell Park Comprehensive Cancer Center, Stanford University, University of Southern California, Medical College of Wisconsin, National Marrow Donor Program, University of North Carolina Health Care
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: U.S. Department of Defense, National Institutes of Health, Health Resources and Services Administration, U.S. Navy, National Heart, Lung, and Blood Institute, Office of Naval Research, National Institute of Mental Health, NIH Office of the Director, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Common Fund
Awards: G1360182821, G1387388519, Minor Histocompatibility Antigen T Cell Targeting in Acute Myeloid Leukemia, Genetic susceptibility to unrelated donor stem cell transplant-related mortality, G2322063371, G2551907125, G3033882165, G3605539328, G3745029439, G4664739311, Cure Sickle Cell, G4910750673, G5233146051, G5236668762, G536687284, G5520316217, G5735794559, G6238506038, G6659488911, G6932420423, G6979277618, G715986205, G7296398813, G7297870625, G7309481926, G746619137, G7733677619, G7949979095, G8148934282, G8245670873, Immuno-Oncology Translation Network (IOTN): Cellular Immunotherapy Data Resource (CIDR), G8666848461, G870761348, Feedback Control of Respiration Induced Tumor Motion with a Treatment Couch, G8871973681, G8876996369, G9000046206, 1/2A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia, Gvl mHA Specific T Cell Responses Prevent AML Relapse Following Allogeneic Stem Cell Transplantation., A Data Resource for Blood and Marrow Transplants and Adoptive Cellular Therapy Research, Understanding Population Differences in Cancer: The MEC Study, Blood and Marrow Transplant Clinical Trials Network DCC- The Medical College of Wisconsin, Inc.
OpenAlex ID: W4310944692