Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

ABSTRACT: Persistent therapy-resistant leukemic progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrate that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach we characterized the antigenic landscape of patient LPCs and identify AML/LPC-associated HLA-presented antigens as well as mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Peripheral Blood Mononuclear Cell

DISEASE(S): Acute Myeloid Leukemia

SUBMITTER: Annika Nelde

LAB HEAD: Juliane S. Walz

PROVIDER: PXD038691 | Pride | 2023-08-23

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Immune surveillance of acute myeloid leukemia is mediated by HLA-presented antigens on leukemia progenitor cells

Project description:Persistent therapy-resistant leukemia progenitor cells (LPC) are a main cause of disease relapse and recurrence in acute myeloid leukemia (AML). Specific LPC-targeting therapies may thus improve treatment outcome of AML patients. We demonstrated that LPCs present human leukocyte antigen (HLA)-restricted cancer antigens that induce T cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LPCs and identified AML/LPC-associated HLA-presented antigens including mutation-derived and cryptic neoepitopes as prime targets for development of T cell-based immunotherapeutic approaches. We observed frequent spontaneous memory T cells targeting these AML/LPC-associated antigens in AML patients and showed that antigen-specific T cell recognition and HLA class II immunopeptidome diversity impacts clinical outcome. Our results pave the way for implementation of AML/LPC-associated antigens for T cell-based immunotherapeutic approaches to specifically target and eliminate residual LPCs in AML patients.

2023-08-23 | GSE235080 | GEO

The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy

Project description:Anti-leukemia immunity plays an important role for disease control and maintenance of tyrosine kinase inhibitor (TKI)-free remission in chronic myeloid leukemia (CML). Antigen-specific immunotherapy holds promise to strengthen immune control in CML, but requires the identification of CML-associated targets. In this study, we used a mass spectrometry-based approach to identify naturally presented HLA class I- and class II-presented peptides in 20 primary CML samples. Comparative HLA ligandome profiling using a comprehensive dataset of different hematological benign specimen delineated a novel panel of frequently expressed CML-exclusive peptides. These non-mutated target antigens are of particular relevance since our extensive data-mining approach demonstrated absence of naturally presented BCR-ABL- and ABL-BCR-derived HLA-presented peptides and the lack of frequent tumor-exclusive presentation of predescribed cancer/testis and leukemia-associated antigens. Functional characterization revealed spontaneous T-cell responses against the newly identified CML-associated peptides in CML patients and their ability to de novo induce multifunctional and cytotoxic antigen-specific T cells in healthy volunteers and CML patients. This characterizes these antigens as prime candidates for T cell-based immunotherapy approaches that may prolong TKI-free survival and even mediate cure of CML patients.

2018-12-11 | PXD010450 | Pride

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

Project description:Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8+ T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance. Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell–based immunotherapy of MM.

2022-07-19 | PXD035324 | Pride

Unsupervised mining of HLA-I peptidomes reveals unsuspected false positives and new binding motifs

Project description:Modern antigen vaccine designs and studies of human leukocyte antigen (HLA)-mediated immune responses rely heavily on the knowledge of HLA allele-specific binding motifs and computational prediction of antigen-HLA binding affinity. Breakthroughs in HLA peptidomics have considerably expanded the databases of natural HLA antigens and enabled detailed characterizations of antigen-HLA binding specificity. However, cautions must be made when analyzing HLA peptidomics data because identified peptides may be contaminants or may weakly bind to the HLA molecules. Here, a hybrid de novo peptide sequencing approach was applied to large-scale mono-allelic HLA peptidomics datasets to uncover new antigens and refine current knowledge of HLA binding motifs. Up to 12-40% contaminations in the form of tryptic peptides were identified in the peptidomics data of HLA alleles whose binding motifs do not involve an arginine or a lysine at the C-terminus. Thousands of these peptides were reported in a community database as positive antigens and might be erroneously used to train prediction models. Furthermore, unsupervised clustering of identified antigens not only revealed additional binding motifs for several HLA class I alleles but also effectively isolated outliers which were confirmed to be false positives in a binding experiment. Overall, our findings expanded the knowledge of HLA binding specificity and indicated that a more careful HLA peptidomics data interpretation protocol is needed to ensure the high quality of community antigen databases.

2021-09-17 | PXD028088 | Pride

Immunoprecipitation methods impact the peptide repertoire in immunopeptidomics

Project description:T cell-based immunotherapies, which have become a promising treatment approach for cancer patients, rely on the identification of human leukocyte antigen (HLA)-presented peptides. Mass spectrometry-based immunopeptidomics is the state-of-the-art method for the identification of clinically relevant naturally presented HLA-restricted tumor-associated antigens. In the last years, different methods for the immunoprecipitation-based isolation of HLA-presented peptides have been developed and are used in the field. Here, we performed a comparison of a column-based with a high-throughput 96-well method by analyzing the immunopeptidome of cell lines as well as primary solid and hematological tumor samples. Whereas no differences in the total number of identified peptides were observed, the column-based method identified method-exclusive peptides that featured higher hydrophobicity and exhibited improved predicted immunogenicity. Adding an additional acetonitrile elution step to the 96-well method could partially reduce this hydrophilic shift. In total, we showed that immunopeptidomics data is affected by the immunoprecipitation method used for isolation, which might have a critical impact on the selection of target antigens and has to be considered when selecting clinically relevant targets for the development of T cell-based immunotherapies.

2023-07-05 | PXD041804 | Pride

The HLA ligandome comprises a limited repertoire of O-GlcNAcylated antigens preferentially associated with HLA-B07:02

Project description:Mass-spectrometry based immunopeptidomics has provided unprecedented insights into antigen presentation, not only charting an enormous ligandome of self-antigens, but also cancer neo-antigens and peptide antigens harbouring post-translational modifications. Here we concentrate on the latter, focusing on the small subset of HLA Class I peptides (less than 1%) that has been observed to be post-translationally modified (PTM) by a O-linked N-acetylglucosamine (GlcNAc). Just like neo-antigens these modified antigens may have specific immunomodulatory functions. Here we compiled from literature, and a new dataset originating from JY B cell lymphoblastoid line cells, a concise albeit comprehensive list of O-GlcNAcylated HLA class I peptides. The cumulative list of O-GlcNAcylated HLA peptides originates from diverse datasets, entailing normal and cancer cell lines as well as tissue samples. Interestingly, the overlap in detected O-GlcNAcylated HLA peptides as well as their source proteins is strikingly high. From the compiled list we extract that O-GlcNAcylated HLA Class I peptides are preferentially presented by the HLA-B07:02 allele. This allele accommodates a Proline anchoring site at position 2, and a binding groove that can accommodate the recently proposed consensus sequence for O-GlcNAcylation, P(V/A/T/S)g(S/T). Most of the O-GlcNAcylated HLA peptides originate from nuclear proteins, notably transcription factors. The conclusions drawn from the compiled list, may assist to predict novel O-GlcNAcylated HLA antigens, which will likely be presented best by patients harbouring HLA-B7:02, or related, alleles that uses Proline as anchoring residue.

2021-12-03 | PXD028874 | Pride

Immunopeptidomics-guided warehouse design for peptide-based immunotherapy in chronic lymphocytic leukemia

Project description:In recent years the clinical success of T cell-based immunotherapy approaches has revolutionized treatment of solid tumors and hematological malignancies. However, still some patients do not respond to available therapies at all, others for limited time only. A promising low side-effect approach is peptide-based immunotherapy, which relies on specific immune recognition of tumor-associated human leucocyte antigen (HLA)-presented peptides. In this study, we developed a workflow for the immunopeptidome-guided design of off-the shelf warehouses for personalized peptide vaccines using the example of chronic lymphocyte leukemia (CLL). The so defined warehouses could provide the basis for different T cell-based immunotherapy approaches such as TCR-engineered T cell transfer or multi-peptide vaccinations. The warehouse approach enables a fast and cost-effective way to provide a personalized T cell-based immunotherapeutic approach. The here defined peptide warehouse is already utilized for a personalized multi-peptide vaccine trial (iVAC-XS15-CLL01, NCT04688385).

2021-09-10 | PXD024871 | Pride

DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts

Project description:Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated bythe de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitors (DNMTi) and/or Histone deacetylase transferase inhibitors (HDACi), to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs), encoding for 61,426 open reading frames. Using Immunopeptidomics, we further demonstrate the human leukocyte antigen (HLA) presentation of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We illustrate the potential of the identified t-neoepitopes to elicit a T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48/96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.

2023-08-18 | PXD035750 | Pride

The immunopeptidomic landscape of ovarian carcinoma

Project description:Immunopeptidome analysis of ovarian carcinoma tissues was performed to characterize the HLA class I and class II presented ligandome of this malignancy.

2017-11-02 | PXD007635 | Pride

Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy

Project description:Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8+ T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4+ T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.

2019-10-14 | PXD015748 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data