ORCID Profile
0000-0002-9283-0743
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 09-11-2020
DOI: 10.1038/S41467-020-19464-8
Abstract: Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8 + T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Research Square Platform LLC
Date: 03-08-2022
DOI: 10.21203/RS.3.RS-1890352/V1
Abstract: Cryptic Human Leukocyte Antigen (HLA)-presented peptide identification from unannotated genome sources is a priority for target antigen discovery for development of next generation immunotherapies in cancer. Current immunopeptidomic approaches utilize the integration of transcriptomics data to inform spectral interpretation, however, recent observations that tumour-associated antigen-encoding RNA levels are often low highlights limitations of such proteogenomic approaches 1 . We here employ a de novo sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical HLA-associated peptide sequences (HLAp) in cancer without integration of transcript sequence information. Our strategy integrates HLA binding prediction, peptide retention time prediction, and average local confidence scores culminating in the machine learning model MARS (MHC binding prediction, Average Local Confidence Score, and Retention time integration for improved de novo candidate Selection). We demonstrate increased HLA-I peptide identification sensitivity by benchmarking our model against de novo sequencing alone with a large synthetic HLA-I peptide library dataset. We further define the sensitivity of MARS by reanalysis of a published dataset of high-quality non-canonical HLAp identifications in human cancer cell line and tissue datasets and achieve almost 2-fold improvement of the full sequence recall (FSR) for high quality spectral assignments in comparison to de novo sequencing alone 2 . We minimize the false discovery rate (FDR) through a step-wise peptide sequence mapping strategy and are able to expand the reported non-canonical peptide space with an assignment accuracy above 85.7%. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, non-canonical peptide sequences in primary tumour tissue at reduced FDR, in the absence of transcriptomic sequencing data.
Publisher: Oxford University Press (OUP)
Date: 29-07-2017
DOI: 10.1093/NAR/GKX664
Publisher: eLife Sciences Publications, Ltd
Date: 08-07-2015
DOI: 10.7554/ELIFE.07661
Abstract: We present a novel mass spectrometry-based high-throughput workflow and an open-source computational and data resource to reproducibly identify and quantify HLA-associated peptides. Collectively, the resources support the generation of HLA allele-specific peptide assay libraries consisting of consensus fragment ion spectra, and the analysis of quantitative digital maps of HLA peptidomes generated from a range of biological sources by SWATH mass spectrometry (MS). This study represents the first community-based effort to develop a robust platform for the reproducible and quantitative measurement of the entire repertoire of peptides presented by HLA molecules, an essential step towards the design of efficient immunotherapies.
Publisher: Wiley
Date: 06-2018
Publisher: Wiley
Date: 06-2018
Publisher: Research Square Platform LLC
Date: 20-07-2022
DOI: 10.21203/RS.3.RS-1828302/V1
Abstract: Selective binding of TCR-based therapies that target a single tumour-specific peptide epitope presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive computational modeling. We developed the first experimental platform to de novo identify interactomes of TCR-like molecules directly in human tissues using mass spectrometry. As proof of concept, we confirm the target epitope of a novel MAGE-A4-specific TCR-like antibody. We further determine 16 cross-reactive sequences for ESK1, a TCR-like bispecific antibody recognizing WT-1 with known off-target activity, in healthy liver tissue. We observe strong, off-target-induced T cell activation for 8/16 sequences, demonstrating the high specificity of the approach. Off-target sequences define a previously missed amino acid compensation motif that structurally mimics the target peptide groove coordination and allows for peptide interaction with the engager molecule. We establish the importance of the identified off-target activity by demonstrating 3D liver spheroid killing in the presence of ESK1 and healthy donor PBMC. Finally, we utilize our approach to de-risk our novel MAGE-A4 targeting TCR-like bispecific antibody prior to entering now ongoing clinical trials. We conclude that our strategy offers an accurate, scalable route for de-risking TCR-based therapeutics prior to first-in-human clinical application.
Publisher: Frontiers Media SA
Date: 27-04-2018
Publisher: Wiley
Date: 10-04-2018
Abstract: The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the ER. These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here, naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv) are identified. HIVenv peptides are present at a very small percentage of the overall HLA-B*57:01 peptidome (<0.1%) and both native and posttranslationally modified forms of two distinct HIV peptides are identified. Notably, a peptide bearing a natively encoded C-terminal tryptophan residue is also present in a modified form containing a kynurenine residue. Kynurenine is a major product of tryptophan catabolism and is abundant during inflammation and infection. Binding of these peptides at a molecular level and their immunogenicity in preliminary functional studies are examined. Modest immune responses are observed to the modified HIVenv peptide, highlighting a potential role for kynurenine-modified peptides in the immune response to HIV and other viral infections.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.HRTLNG.2018.09.016
Abstract: Family presence during resuscitation (FPDR), remains inconsistently implemented by emergency personnel. The benefits for family members is well documented, providing opportunities for family to say goodbye, facilitates closure and enables family to provide emotional support to the patient. The aim of this study was to explore the experiences and attitudes of emergency personnel towards FPDR immediately post resuscitation events. A descriptive qualitative design was used to explore the experiences of emergency personnel with FPDR. Data was collected from single rural and metropolitan emergency departments in the state of Victoria, Australia. The participants consisted of nurses and doctors who took active roles during resuscitation events. Following transcription of the audiotaped interviews Creswell's (2003) six step analysis process was employed. A total of 29 interviews of key personnel, following 6 paediatric and 18 adult resuscitation events. Interviews were conducted over a period of two weeks in each venue. The data was organised into six themes following analysis including: care coordinators inconsistently called, gate keepers to implementation, effective communication strategies helping to deliver bad news, life experience generates confidence, allocation of family support person, and family members roles dependent on age of patient. FPDR is common practice in paediatric events however remains inconsistently implemented during adult resuscitations. A designated family support person is essential to successful implementation of FPDR and should be incorporated in to the allocation of the resuscitation team roles during both adult and paediatric resuscitation events. Education and training is important for clinicians to learn essential communication skills, building practice confidence, which is required to successfully implement FPDR.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 04-11-2015
Publisher: American Society for Microbiology
Date: 09-2019
DOI: 10.1128/JVI.00634-19
Abstract: Mass spectrometry (MS)-based approaches are increasingly being employed for large-scale identification of HLA-bound peptides derived from pathogens, but only very limited profiling of the HIV-1 immunopeptidome has been conducted to date. Notably, a growing body of evidence has recently begun to indicate a protective role for HLA-C in HIV-1 infection, which may suggest that despite the fact that levels of HLA-C expression on both uninfected and HIV-1-infected cells are lower than those of HLA-A/B, HLA-C still presents epitopes to CD8 + T cells effectively. To explore this, we analyzed HLA-C*12:02-restricted HIV-1 peptides presented on HIV-1-infected cells expressing only HLA-C*12:02 (a protective allele) using liquid chromatography-tandem MS (LC-MS/MS). We identified a number of novel HLA-C*12:02-bound HIV-1 peptides and showed that although the majority of them did not elicit T cell responses during natural infection in a Japanese cohort, they included three immunodominant epitopes, emphasizing the contribution of HLA-C to epitope presentation on HIV-infected cells.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 10-2011
Publisher: Cold Spring Harbor Laboratory
Date: 17-02-2021
DOI: 10.1101/2021.02.16.431395
Abstract: Human leukocyte antigen (HLA) is highly polymorphic and plays a key role in guiding adaptive immune responses by presenting foreign and self peptides to T cells. Each HLA variant selects a minor fraction of peptides that match a certain motif required for optimal interaction with the peptide-binding groove. These restriction rules define the landscape of peptides presented to T cells. Given these limitations, one might suggest that the choice of peptides presented by HLA is non-random and there is preferential presentation of an array of peptides that is optimal for distinguishing self and foreign proteins. In this study we explore these preferences with a comparative analysis of self peptides enriched and depleted in HLA ligands. We show that HLAs exhibit preferences towards presenting peptides from certain proteins while disfavoring others with specific functions, and highlight differences between various HLA genes and alleles in those preferences. We link those differences to HLA anchor residue propensities and amino acid composition of preferentially presented proteins. The set of proteins that peptides presented by a given HLA are most likely to be derived from can be used to distinguish between class I and class II HLAs and HLA alleles. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Finally, we show that the reported self peptidome preferences of distinct HLA variants can be compensated by combinations of HLA-A/HLA-B and HLA-A/HLA-C alleles in frequent haplotypes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-10-2018
DOI: 10.1126/SCIIMMUNOL.AAR3947
Abstract: A considerable proportion of HLA-I peptides likely derive from cis- and trans-splicing events.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Nicola Ternette.