Genetics of HLA Peptide Presentation and Impact on Outcomes in HLA-Matched Allogeneic Hematopoietic Cell Transplantation

• Type of Material: Article
• Authors: Edmund Waller, Emory University; Charlotte Mcllwaine Story, University of North Carolina; Tao Wang, Medical College of Wisconsin; Vijaya R Bhatt, University of Nebraska Medical Center; Minoo Battiwalla, Sarah Cannon Blood Cancer Network; Sherif M Badawy, Northwestern University; Malek Kamoun, University of Pennsylvania; Loren Gragert, Tulane University; Valerie Brown, Penn State Hershey Children’s Hospital; Lee Ann Baxter-Lowe, Children’s Hospital of Los Angeles; Steven GE Marsh, Anthony Nolan Research Institute; Steven M Gadalla, NIH-NCI Clinical Genetics Branch, Rockville; Johannes Schetelig, University Hospital Carl Gustav Carus, TU Dresden; Joannis Mytilineos,, German National Bone Marrow Donor Registry; David Miklos, Stanford Health Care, California; Michelle Kuxhausen, Center for International Blood and Marrow Transplant Research, Minneapolis; Stephen Spellman, Center for International Blood and Marrow Transplant Research, Minneapolis; Stephanie Lee, Fred Hutchinson Cancer Research Center; Sophie Paczesny, Medical University of South Carolina; Jefferson L Lansford, Walter Reed Natl Mil Med Ctr; Benjamin G Vincent, University of North Carolina; Marcie L Riches, University of North Carolina; Paul M Armistead, University of North Carolina
• Language: English
• Date: 2021-06-28
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jtct.2021.04.003
• Title of Journal or Parent Work: TRANSPLANTATION AND CELLULAR THERAPY
• Volume: 27
• Issue: 7
• Start Page: 591
• End Page: 599
• Keywords: Graft-versus-host disease; RISK; Science & Technology; MINOR HISTOCOMPATIBILITY ANTIGENS; VERSUS-HOST-DISEASE; antigen; HLA; Hematology; RECIPIENTS; BONE-MARROW; Minor histocompatibility; MHC CLASS-I; UNRELATED-DONOR; Peptide epitope binding; Immunology; Life Sciences & Biomedicine; Transplantation; DISPARITY; MISMATCHES; BLOOD

Abstract

Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic “distance” between HLA-matched donors and recipients is relatively constrained. From these 2 observations, it is possible that the HLA type for a donor-recipient pair (DRP) would provide a surrogate measurement of the number of predicted mHAs, which could be related to GVHD risk. Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide-binding efficiency can be calculated for individual DRP based on the pair's HLA type. The purpose of this study was to test whether cumulative peptide-binding efficiency is associated with the risk of acute GVHD (aGVHD) or relapse. In this retrospective Center for International Blood and Marrow Transplant Research study, a total of 3242 HLA-matched DRPs were analyzed for predicted cumulative peptide-binding efficiency using their HLA types and were divided into tertiles based on their scores. Univariable and multivariable analyses was performed to test for associations between cumulative peptide-binding efficiency for DRPs, divided into the HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival, disease-free survival, and transplantation-related mortality. Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide-binding frequencies ranging from 0.1% to 3.8% of the full peptidome, and HLA class II molecules had peptide-binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41%, and 45% for HLA class I (P =. 336) and 44%, 41%, and 42% for HLA class II (P =. 452). The cumulative incidences of relapse at 3 years for MUD transplant recipients were 36%, 38%, and 38% for HLA class I (P =. 533) and 37%, 37%, and 38% for HLA class II (P =. 896). The findings were similar for MRD transplant recipients. Multivariable analysis did not identify any impact of peptide-binding efficiency on aGVHD or relapse in MUD or MRD transplant recipients. Whereas GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide-binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker, or it is possible that GVHD is driven by a subset of immunogenic mHAs. Further research should be directed at direct mHA epitope and immunogenicity prediction.