Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer
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PROVIDER: PRJNA599422 | ENA |
REPOSITORIES: ENA
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Project description:Tumor epitopes – peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples. These included primary normal and chronic lymphocytic leukemia (CLL) B cells, patient-derived primary glioblastoma (GBM) and melanoma cell cultures, primary healthy melanocytes, as well as established colon carcinoma and melanoma cell lines. These also included B721.221 cells, the parental cell line previously used to generate 92 single HLA allele-expressing lines from which we collected mono-allelic MHC I immunopeptidome data. We developed a hierarchical approach to identify translated novel unannotated open reading frames that leverages the large amount of Ribo-seq data we have generated in order to uncover lowly expressed nuORFs, while also preserving tissue specificity. We constructed a database of novel unannotated ORFs (nuORFdb) and used it to analyze mass spectrometry datasets of MHC I-bound peptides, where we detected peptides from 3,555 nuORFs. Additionally, we used nuORFdb to identify cancer-specific nuORFs, as well as nuORFs harboring cancer-specific somatic variants as potential sources of neoantigens in cancer. *This repository contains data from the publicly available cell lines used in this study, including B721.221 cells, A375 cells, HCT116 cells and primary healthy melanocytes (Thermo C0025C). The data pertaining to primary patient samples that are part of this study is deposited in dbGaP.
2020-08-01 | GSE143263 | GEO
Project description:Ouspenskaia T, Law T, Clauser KR, Klaeger S, Sarkizova S, Aguet F, Li B, Christian E, Knisbacher BA, Le P, Hartigan CR, Keshishian H, Oliveira G, Zhang W, Chow YT, Ji Z, Shukla SA, Bachireddy P, Getz G, Hacohen N, Keskin DB, Carr SA, Wu CJ, Regev A. Tumor epitopes, peptides that are presented on surface-bound MHC I proteins, provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.
2020-01-10 | MSV000084787 | MassIVE
Project description:Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance
| PRJNA471521 | ENA
Project description:MHC class II proteins mediate cross-species entry of bat influenza viruses
| PRJNA803440 | ENA
Project description:The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. Rapidly degraded nascent polypeptides (DRiPs) provide many class I peptide ligands. By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. We show that 60S ribosomal proteins L6 (RPL6) and RPL28, which are adjacent on the ribosome, play opposite roles in generating an influenza A virus encoded peptide. RPL6 depletion decreases ubiquitin-dependent peptide presentation, while RPL28 depletion increases ubiquitin-dependent and -independent peptide presentation. 40S ribosomal protein S28 (RPS28) knockdown increases total peptide supply in uninfected cells by increasing DRiP synthesis from non-canonical translation of “untranslated” regions and non-AUG start codons, and sensitizes tumor cells for T cell targeting. RPL23 knocKDut decreases overall peptide supply, impairing T cell recognition of tumor cells. Our findings raise the possibility of modulating immunosurveillance by pharmacologically targeting ribosomes.
2019-01-21 | GSE114484 | GEO
Project description:The MHC region encodes HLA genes and is the most complex region in the human genome. The extensive polymorphic nature of the HLA hinders accurate localization and functional assessment of disease risk loci within this region. Using targeted capture sequencing and constructing individualized genomes for transcriptome alignment, we identified 908 novel transcripts within the human MHC region. These include 593 novel isoforms of known genes, 137 antisense strand RNAs, 119 novel long intergenic noncoding RNAs, and 5 transcripts of 3 novel putative protein-coding human endogenous retrovirus genes. We revealed allele-dependent expression imbalance involving 88% of all heterozygous transcribed single nucleotide polymorphisms throughout the MHC transcriptome. Among these variants, we show that the genetic variant associated with Behc ̧et’s disease in the HLA-B/MICA region, which tags HLA-B*51, is within novel long intergenic noncoding RNA transcripts that are exclusively expressed from the haplotype with the protective but not the disease risk allele. Further, we showed that the transcriptome within the MHC region can be defined by 14 distinct coexpression clusters, with evidence of coregulation by unique transcription factors in at least 9 of these clusters. Our data suggest a very complex regulatory map of the human MHC, and can help uncover functional consequences of disease risk loci in this region.
2018-05-02 | GSE108663 | GEO
Project description:Zoonotic influenza A viruses of avian origin can cause severe disease in individuals, or even global pandemics, and thus pose a threat to human populations. Waterfowl and shorebirds are believed to be the reservoir for all influenza A viruses, but this has recently been challenged by the identification of novel influenza A viruses in bats. The major bat influenza A virus envelope glycoprotein, haemagglutinin, does not bind the canonical influenza A virus receptor, sialic acid or any other glycan, despite its high sequence and structural homology with conventional haemagglutinins. This functionally uncharacterized plasticity of the bat influenza A virus haemagglutinin means the tropism and zoonotic potential of these viruses has not been fully determined. Here we show, using transcriptomic profiling of susceptible versus non-susceptible cells in combination with genome-wide CRISPR-Cas9 screening, that the major histocompatibility complex class II (MHC-II) human leukocyte antigen DR isotype (HLA-DR) is an essential entry determinant for bat influenza A viruses. Genetic ablation of the HLA-DR α-chain rendered cells resistant to infection by bat influenza A virus, whereas ectopic expression of the HLA-DR complex in non-susceptible cells conferred susceptibility. Expression of MHC-II from different bat species, pigs, mice or chickens also conferred susceptibility to infection. Notably, the infection of mice with bat influenza A virus resulted in robust virus replication in the upper respiratory tract, whereas mice deficient for MHC-II were resistant. Collectively, our data identify MHC-II as a crucial entry mediator for bat influenza A viruses in multiple species, which permits a broad vertebrate tropism.
2022-02-04 | GSE196122 | GEO
Project description:Custom DNA microarrays reveal diverse binding preferences of proteins and small molecules to thousands of G-quadruplexes
| PRJNA551269 | ENA