In Silico Analysis of the Minor Histocompatibility Antigen Landscape Based on the 1000 Genomes Project

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is routinely used to treat hematopoietic malignancies. The eradication of residual tumor cells during engraftment is mediated by donor cytotoxic T lymphocytes reactive to alloantigens. In a HLA-matched transplantation context, alloantigens are encoded by various polymorphic genes situated outside the HLA locus, also called minor histocompatibility antigens (MiHAs). Recently, MiHAs have been recognized as promising targets for post-transplantation T-cell immunotherapy as they have several appealing advantages over tumor-associated antigens (TAAs) and neoantigens, i.e., they are more abundant than TAAs, which potentially facilitates multiple targeting; and unlike neoantigens, they are encoded by germline polymorphisms, some of which are common and thus, suitable for off-the-shelf therapy. The genetic sources of MiHAs are nonsynonymous polymorphisms that cause differences between the recipient and donor proteomes and subsequently, the immunopeptidomes. Systematic description of the alloantigen landscape in HLA-matched transplantation is still lacking as previous studies focused only on a few immunogenic and common MiHAs. Here, we perform a thorough in silico analysis of the public genomic data to classify genetic polymorphisms that lead to MiHA formation and estimate the number of potentially available MiHA mismatches. Our findings suggest that a donor/recipient pair is expected to have at least several dozen mismatched strong MHC-binding SNP-associated peptides per HLA allele (116 ± 26 and 65 ± 15 for non-related pairs and siblings respectively in European populations as predicted by two independent algorithms). Over 70% of them are encoded by relatively frequent polymorphisms (minor allele frequency > 0.1) and thus, may be targetable by off-the-shelf therapeutics. We showed that the most appealing targets (probability of mismatch over 20%) reside in the asymmetric allele frequency region, which spans from 0.15 to 0.47 and corresponds to an order of several hundred (213 ± 47) possible targets per HLA allele that can be considered for immunogenicity validation. Overall, these findings demonstrate the significant potential of MiHAs as targets for T-cell immunotherapy and emphasize the need for the systematic discovery of novel MiHAs.

Can Graft vs. Leukemia Effect Be Uncoupled From Graft vs. Host Disease? An Examination of Proportions

“…The SNPs when compared to the mutations used to estimate TSA, are much larger in number, indicating that mHA may provide the dominant antigen background in terms of generating alloreactivity following HCT. Similar data regarding the extent of genomic variation between transplant donors and recipients have been reported by other groups investigating genomic variation in transplant recipients, in both solid organ transplants (48) and in HCT (49)(50)(51)(52)(53), as well as in models predicting GVL specific libraries (54). This abundance of SNPs across the exome in unique HCT donor-recipient pairs is an eye-opening finding compared to the average 10 mutations per hematologic neoplasm.…”

Optimized Whole Genome Association Scanning for Discovery of HLA Class I-Restricted Minor Histocompatibility Antigens

“…As reported by Bykova et al (30), SNPs with a high probability of mismatch between patient and donor have allele frequencies between 0.15 and 0.47. Our data showed that for seven common HLAs, all minor histocompatibility antigens encoded by SNPs with these allele frequencies can be detected with the new panel of EBV-LCLs from the 1000 Genomes Project.…”

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

“…In theory, selective depletion of HLA-A and HLA-B while preserving HLA-C on CAR T-cells could potentially limit the essential pool of allogeneic "off-the-shelf" cell products to several dozens or even less. Nevertheless, allogeneic cells with retained expression of either HLA class I or II still hold a significant threat of immunogenicity in a patient due to minor histocompatibility antigens (MiHAgs) [138] derived from near-infinite diversity of single nucleotide polymorphisms (SNPs) that vary in the donor and a patient [139]. These antigens contribute to GvHD (in hematopoietic stem cell transplantation) or transplant rejection (in solid organ recipients) and could also limit the persistence of allogeneic CAR T-cells.…”