Specific T Cell Responses against Minor Histocompatibility Antigens Cannot Generally Be Explained by Absence of Their Allelic Counterparts on the Cell Surface

Bijen, Helena M.; Hassan, Chopie; Kester, Michel G.D.; Janssen, George M.C.; Hombrink, Pleun; Ru, Arnoud H. de; Drijfhout, Jan W.; Meiring, Hugo D.; Jong, Ad P. de; Falkenburg, J.H. Frederik; Jiménez, Connie R.; Heemskerk, Mirjam H.M.; Veelen, Peter A. van

doi:10.1002/pmic.201700250

Cited by 20 publications

(16 citation statements)

References 29 publications

(34 reference statements)

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“…For known MiHAs, the independent discovery of two variants of the same MiHA is very unlikely as only a small number of MiHAs have been discovered and the systematic investigation of counterpart peptide immunogenicity is usually not performed. Recent quantitative MS experiments, focused on specific MiHAs rather than the whole immunopeptidome, confirmed that some MiHAs, previously thought to be dominant, were actually co-dominant ( 47 ). If the MiHA co-dominant/dominant ratio suggested by in silico analysis is valid, approximately half of the MiHAs would be categorized as co-dominant and the number of targetable antigens would substantially increase.…”

Section: Resultsmentioning

confidence: 88%

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

2018

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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.

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Section: Resultsmentioning

confidence: 88%

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

2018

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“…Absolute quantification of pMHCs to date is most commonly performed by comparing endogenous levels of pMHCs to exogenous peptide standards, again failing to account for sample losses [21][22][23][24] . Losses can be accounted for with internal pMHC standards, but require laborious refolding of pMHCs for every target of interest 19,25 . Nevertheless, this approach relies on single point calibration, ignoring the effects of ion suppression, thereby inaccurately estimating absolute pMHC levels in quantitative analyses.…”

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confidence: 99%

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

et al. 2020

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Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire's response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking normalization controls. We describe an experimental platform that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma cell lines to profile the immunopeptidome response to CDK4/6 inhibition and interferon-γknown modulators of antigen presentation uncovers treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.

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“…For some MiHAs both alleles encode MHC-presented peptides, potentially making them immunogenic in both directions (co-dominant). In this case, T-cells discriminate peptides by a single amino acid difference (10). Up to date over 60 MiHAs have been discovered.…”

Section: Introductionmentioning

confidence: 99%

Rapid Multiplex Genotyping of 20 HLA-A*02:01 Restricted Minor Histocompatibility Antigens

et al. 2019

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A subset of MHC-associated self-peptides presented by the recipient's cells and immunologically foreign to the donor can induce an allogeneic immune response after hematopoietic stem cell transplantation (HSCT). These immunogenic peptides originate from the genomic polymorphisms and are known as minor histocompatibility antigens (MiHA). MiHA mismatches trigger the post-transplant immune response, which could manifest in both the deleterious “graft-vs.-host” disease and the beneficial “graft-vs.-leukemia” effect. Importantly, some MiHAs are considered to be promising targets for posttransplant T-cell immunotherapy of hematopoietic malignancies. This creates a demand for a robust and fast approach to genotyping MiHA-encoding polymorphisms. We report a multiplex real-time PCR method for the genotyping of 20 polymorphisms that are encoding HLA-A * 02:01-restricted MiHAs. This method uses allele-specific primers and gene-specific hydrolysis probes. In 1 h it allows for the detection of MiHA mismatches in a donor-recipient pair without the need for electrophoresis, sequencing, or other time-consuming techniques. We validated the method with Sanger and NGS sequencing and demonstrated good performance over a wide range of DNA concentrations. We propose our protocol as a fast and accurate method of identifying mismatched MiHAs. The information on the MiHA mismatches is useful for studying the allogeneic immune response following HSCT and for selecting the targets for post-transplant T-cell therapy.

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Specific T Cell Responses against Minor Histocompatibility Antigens Cannot Generally Be Explained by Absence of Their Allelic Counterparts on the Cell Surface

Cited by 20 publications

References 29 publications

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

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

Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

Rapid Multiplex Genotyping of 20 HLA-A*02:01 Restricted Minor Histocompatibility Antigens

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