The HLA ligandome of oropharyngeal squamous cell carcinomas reveals shared tumor-exclusive peptides for semi-personalized vaccination
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PROVIDER: EGAS00001006477 | EGA |
REPOSITORIES: EGA
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Project description:Oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed in 93,000 patients worldwide per year and 51,000 annual deaths can be attributed to this disease. OPSCCs are either human papillomavirus associated (HPV-positive) cancers or non-virally induced, primarily tobacco and alcohol associated (HPV-negative) cancers. MS analysis enabled the identification of naturally HLA-presented peptides in OPSCC tumor tissue. By comparative profiling against benign HLA ligandomic datasets, we demonstrated that tumor-associated peptides are HLA-presented on the cell surfaces of OPSCCs. The established warehouse of OPSCC-associated peptides can be used for downstream immunogenicity testing and peptide-based immunotherapy in (semi-) personalized strategies.
2023-02-27 | PXD033383 | Pride
Project description:T cell-mediated immunity seems to play a critical role against SARS-CoV-2 infection and establishing protective memory. Yet the repertoire of viral epitopes responsible for activation of T cell responses remains mostly unknown. Identification and characterization of viral peptides presented on class I human leukocyte antigen (HLA-I) will reveal the viral signatures as seen by cytotoxic T cells that can then be harnessed for the development of effective vaccines. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two human cell lines at different times post-infection using mass spectrometry. We found HLA-I peptides derived not only from canonical ORFs, but also from internal out-of-frame ORFs in Spike and Nucleoprotein not currently captured by vaccine approaches. Whole proteome analysis revealed that expression of ubiquitination pathway proteins, and the proteasome maturation protein, POMP, were significantly altered in infected cells. Retrospective analysis of computational predictions highlighted shortcomings of in silico-only approaches in recovering the observed viral epitopes. Finally, given the experimental evidence for endogenous processing and presentation of the viral peptides we detected, we estimated that at least one HLA-A, -B, or -C allele is covered by at least one peptide for 99% of the population. These biological insights and the list of naturally presented SARS-CoV-2 peptides will facilitate data-driven selection of peptides for immune monitoring and vaccine development.
2020-10-08 | GSE159191 | GEO
Project description:LC-MS/MS-based identification of HLA-peptides is poised to provide a deep understanding of the rules underlying antigen presentation. However, a key obstacle limiting the utility of MS data is the ambiguity arising from the co-expression of multiple HLA alleles. Here, we introduce a strategy for profiling the HLA ligandome one allele at a time. By using cell lines expressing a single HLA allele, optimizing immunopurifications, and developing a novel spectral search algorithm, we identified thousands of peptides bound to 16 different HLA class I alleles. These data enabled the discovery of novel binding motifs, and an integrative analysis quantifying the contribution of factors critical to epitope presentation, such as protein cleavage and gene expression. We trained neural network prediction algorithms with our large dataset (>24,000 peptides) and outperformed algorithms trained on datasets of peptides with measured affinities. We thus demonstrate a scalable strategy for systematically learning the rules of endogenous antigen presentation.
2017-02-21 | GSE93315 | GEO
Project description:Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-associated peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs associated with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-associated ligands with 1.5-fold improvement in positive predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were observed experimentally in 11 patient-derived tumor cell lines.
2019-12-16 | GSE131267 | GEO
Project description:HLA-E molecules can present self and pathogen-derived peptides to both NK-cells and T-cells. T-cells that recognize HLA-E peptides via their T-cell receptor (TCR) are termed donor-unrestricted T-cells due to restricted allelic variation of HLA-E. The composition and repertoire of HLA-E TCRs is not known so far. We performed TCR sequencing on CD8+ T-cells from 21 individuals recognizing HLA-E tetramers (TM) folded with 2 Mtb HLA-E restricted peptides. We sorted HLA-E Mtb TM+ and TMCD8+ T-cells directly ex vivo and performed bulk RNA-sequencing and single cell TCR sequencing. The identified TCR repertoire was diverse and showed no conservation between and within individuals. TCRs selected from our single cell TCR sequencing data could be activated upon HLA-E/peptide stimulation, although not robust, reflecting potentially weak interactions between HLA-E peptide complexes and TCRs. Thus, HLA-E Mtb specific T-cells have a highly diverse TCR repertoire.
2024-02-04 | GSE236154 | GEO
Project description:Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T-cell antigens in medulloblastoma. We mapped the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and performed comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma proved to be a rich source of novel tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins were subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) was rare. Functional testing of top-ranking novel candidate antigens demonstrated the induction of peptide-specific T-cell responses, supporting their potential for T-cell immunotherapy. This study is an in-depth mapping of naturally presented T-cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data led to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma.
2024-08-24 | GSE238195 | GEO
Project description:Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T-cell antigens in medulloblastoma. We mapped the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and performed comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma proved to be a rich source of novel tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins were subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) was rare. Functional testing of top-ranking novel candidate antigens demonstrated the induction of peptide-specific T-cell responses, supporting their potential for T-cell immunotherapy. This study is an in-depth mapping of naturally presented T-cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data led to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma.
2024-08-24 | GSE250586 | GEO
Project description:Treatment of cancer cells with anti-cancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumorâs gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anti-cancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited anti-tumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug. The transcriptomes, proteomes and HLA peptidomes of the U-87, T98G and LNT-229 GBM human cell lines were analyzed before and after treatment with Decitabine. Overall, the RNA-Seq transcriptome analyses resulted in the identification of above 26000 transcripts, the proteome analyses identified about 7500 proteins and the HLA class I peptidome analyses resulted in above 25000 identified HLA peptides. Two biological repetitions of the transcriptome, three of the proteome and three of the HLA peptidome were performed with each of the cell lines and treatment, resulting in highly reproducible datasets.
2016-07-19 | E-GEOD-80137 | biostudies-arrayexpress
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
Project description:Genome wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by an exon microarray study. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders. There were 20 anterior cingulate postmortem brain samples that were extracted for total RNA, and analyzed using Affymetrix Exon Array (bipolar disorder subjects n = 9, controls n = 11).
2016-02-25 | E-GEOD-78246 | biostudies-arrayexpress