Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase

Kremer, Anita N.; Bausenwein, Judith; Lurvink, Ellie G.A.; Kremer, Andreas E.; Rutten, Caroline E.; Bergen, Cornelis A.M. van; Kretschmann, Sascha; Meijden, Edith van der; Honders, M. Willy; Mazzeo, Daniela; Watts, Colin; Mackensen, Andréas; Falkenburg, J.H. Frederik; Griffioen, Marieke

doi:10.3389/fimmu.2020.00381

Cited by 8 publications

(10 citation statements)

References 35 publications

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“…Using mass spectrometry, we validated a total of 24 novel GvL mHAs, an increase from the 13 GvL mHAs that have been discovered since Els Goulmy et al reported the first discovered GvL mHA, HA-1, in 1983 1,25,28,[30][31][32][33] . The 16 novel GvL mHAs found for HLA-A*02:01 together cover 98.8% of HLA-A*02:01-positive patients in the DISCOVeRY-BMT dataset, the three for HLA-B*35:01 cover 60.7% of HLA-B*35-:01-positive DISCOVeRY-BMT patients, and the five for HLA-C*07:02 cover 78.9% of HLA-C*07:02-positive DISCOVeRY-BMT patients.…”

Section: Discussionmentioning

confidence: 97%

“…The copyright holder for this preprint this version posted August 15, 2022. ; https://doi.org/10.1101/2022.08.12.503667 doi: bioRxiv preprint cell responses against them will lead to GvL effects without GvHD. Approximately 55 mHAs have been reported to date, including 13 validated GvL mHAs, and clinical trials of mHA-targeted cellular immunotherapies and vaccines have been performed [25][26][27][28][29][30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

“…GvL mHAs are defined as mHAs that are only expressed in hematopoietic tissue, so T cell responses against them will lead to GvL effects without GvHD. Approximately 55 mHAs have been reported to date, including 13 validated GvL mHAs, and clinical trials of mHA-targeted cellular immunotherapies and vaccines have been performed [25][26][27][28][29][30][31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

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Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Olsen

Jadi

Entwistle

et al. 2022

Preprint

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T cell responses to minor histocompatibility antigens (mHAs) mediate graft versus leukemia (GvL) effects and graft versus host disease (GvHD) in allogeneic hematopoietic cell transplant (alloHCT). Therapies that boost T cell responses improve the efficacy of alloHCT; however, these have been 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 SNP association studies. We report here the discovery of a large set of novel GvL mHAs based on predicted peptide immunogenicity, restriction of expression to hematopoietic tissue or GvHD target organs, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT dataset of 3233 alloHCT DRPs. The total number of predicted mHAs and count within each class of predicted mHAs significantly differed by recipient genomic ancestry group, with European American>Hispanic>African American for each. The number of mHAs also differed markedly by HLA allele, even among alleles of the same gene. 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 then used mass spectrometry to search for high population frequency mHAs for three common HLA alleles. We validated a total of 24 novel predicted GvL mHAs that cumulatively are found 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 also confirmed in vivo immunogenicity of one example novel mHA via coculture of healthy human CD8 T cells with mHA-pulsed dendritic cells. This work demonstrates that identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics to larger numbers of patients.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Olsen

Jadi

Entwistle

et al. 2022

Preprint

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“…It is therefore advisable to test T-cell recognition of the wt version to at least avoid cross-reactivity on use of a neoepitope-based vaccine or T-cell transfer. In regard to CARS2, which shows a limited amount of cross-reactivity against the wt epitope, we suggest that for this particular antigen, discrimination between the mutated and wt antigen be determined by differential processing, [42][43][44] because retroviral expression of full-length CARS2 in MCF-7 cells did not lead to T-cell recognition and exposure of APCs to tumor cell lysates resulted in specific presentation of mutant CARS2.…”

Section: Open Accessmentioning

confidence: 96%

Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy

Reimann

Nguyen²,

Sanborn³

et al. 2021

J Immunother Cancer

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BackgroundTherapeutic regimens designed to augment the immunological response of a patient with breast cancer (BC) to tumor tissue are critically informed by tumor mutational burden and the antigenicity of expressed neoepitopes. Herein we describe a neoepitope and cognate neoepitope-reactive T-cell identification and validation program that supports the development of next-generation immunotherapies.MethodsUsing GPS Cancer, NantOmics research, and The Cancer Genome Atlas databases, we developed a novel bioinformatic-based approach which assesses mutational load, neoepitope expression, human leukocyte antigen (HLA)-binding prediction, and in vitro confirmation of T-cell recognition to preferentially identify targetable neoepitopes. This program was validated by application to a BC cell line and confirmed using tumor biopsies from two patients with BC enrolled in the Tumor-Infiltrating Lymphocytes and Genomics (TILGen) study.ResultsThe antigenicity and HLA-A2 restriction of the BC cell line predicted neoepitopes were determined by reactivity of T cells from HLA-A2-expressing healthy donors. For the TILGen subjects, tumor-infiltrating lymphocytes (TILs) recognized the predicted neoepitopes both as peptides and on retroviral expression in HLA-matched Epstein-Barr virus–lymphoblastoid cell line and BC cell line MCF-7 cells; PCR clonotyping revealed the presence of T cells in the periphery with T-cell receptors for the predicted neoepitopes. These high-avidity immune responses were polyclonal, mutation-specific and restricted to either HLA class I or II. Interestingly, we observed the persistence and expansion of polyclonal T-cell responses following neoadjuvant chemotherapy.ConclusionsWe demonstrate our neoepitope prediction program allows for the successful identification of neoepitopes targeted by TILs in patients with BC, providing a means to identify tumor-specific immunogenic targets for individualized treatment, including vaccines or adoptively transferred cellular therapies.

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“…Recently, SNP-induced differential processing was also found for an HLA-II restricted minor H antigen (95), indicating that development of HLA-II epitope processing prediction algorithms may be valuable for future identification of immunogenic HLA-II presented antigens.…”

Section: Differential Peptide Processing and Presentation Is A Major mentioning

confidence: 99%

The Connection Between Minor H Antigens and Neoantigens and the Missing Link in Their Prediction

2020

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For hundreds of thousands of years, the human genome has extensively evolved, resulting in genetic variations in almost every gene. Immunological reflections of these genetic variations become clearly visible after an allogeneic stem cell transplantation (allo-SCT) as minor Histocompatibility (H) antigens. Minor H antigens are peptides cleaved from genetically encoded variable protein regions after which they are presented at the cell surface by HLA molecules. After allo-SCT with minor H antigen mismatches between donor and recipient, donor T cells recognize the minor H antigens of the recipient as foreign, evoking strong alloreactive immune responses. Studies in the late eighties have discovered that a subset of minor H antigens are encoded by hematopoietic system-specific genes. After allo-SCT, this subset is strictly expressed on the hematopoietic malignant cells and was therefore the first well-defined highly immunogenic group of tumor-specific antigens. In the last decade, neoantigens derived from genetic mutations in tumors have been identified as another group of immunogenic tumor-specific antigens. Therefore, hematopoietic minor H antigens and neoantigens are therapeutic equivalents. This review will connect our current knowledge about the immune biology and identification of minor H antigens and neoantigens leading to novel conclusions on their prediction.

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Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase

Cited by 8 publications

References 35 publications

Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy

The Connection Between Minor H Antigens and Neoantigens and the Missing Link in Their Prediction

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