PMID- 38253617 OWN - NLM STAT- MEDLINE DCOM- 20240124 LR - 20240313 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 15 IP - 1 DP - 2024 Jan 22 TI - MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer. PG - 661 LID - 10.1038/s41467-023-44460-z [doi] LID - 661 AB - Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue. CI - (c) 2024. The Author(s). FAU - Liao, Hanqing AU - Liao H AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Barra, Carolina AU - Barra C AUID- ORCID: 0000-0002-6836-4906 AD - Technical University Denmark, Copenhagen, Denmark. FAU - Zhou, Zhicheng AU - Zhou Z AUID- ORCID: 0000-0001-9137-7951 AD - Universite Paris Cite, Institut Cochin, CNRS, INSERM, 75014, Paris, France. FAU - Peng, Xu AU - Peng X AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. FAU - Woodhouse, Isaac AU - Woodhouse I AUID- ORCID: 0000-0002-8221-7697 AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Tailor, Arun AU - Tailor A AUID- ORCID: 0000-0002-9698-3480 AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Parker, Robert AU - Parker R AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Carre, Alexia AU - Carre A AUID- ORCID: 0000-0001-8144-7194 AD - Universite Paris Cite, Institut Cochin, CNRS, INSERM, 75014, Paris, France. FAU - Borrow, Persephone AU - Borrow P AUID- ORCID: 0000-0002-3877-9780 AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Hogan, Michael J AU - Hogan MJ AUID- ORCID: 0000-0002-6244-2993 AD - Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. FAU - Paes, Wayne AU - Paes W AUID- ORCID: 0000-0002-0529-2765 AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. FAU - Eisenlohr, Laurence C AU - Eisenlohr LC AUID- ORCID: 0000-0002-8475-7910 AD - Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. AD - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. FAU - Mallone, Roberto AU - Mallone R AUID- ORCID: 0000-0002-9846-8861 AD - Universite Paris Cite, Institut Cochin, CNRS, INSERM, 75014, Paris, France. AD - Assistance Publique Hopitaux de Paris, Service de Diabetologie et Immunologie Clinique, Cochin Hospital, 75014, Paris, France. FAU - Nielsen, Morten AU - Nielsen M AUID- ORCID: 0000-0001-7885-4311 AD - Technical University Denmark, Copenhagen, Denmark. FAU - Ternette, Nicola AU - Ternette N AUID- ORCID: 0000-0002-9283-0743 AD - The Jenner Institute, University of Oxford, Oxford, OX3 7BN, UK. nicola.ternette@ndm.ox.ac.uk. AD - Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK. nicola.ternette@ndm.ox.ac.uk. AD - University of Utrecht, Department of Pharmaceutical Sciences, 3584 CH, Utrecht, The Netherlands. nicola.ternette@ndm.ox.ac.uk. LA - eng GR - R01 AI118549/AI/NIAID NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - 28736/CRUK_/Cancer Research UK/United Kingdom GR - R21 AI153978/AI/NIAID NIH HHS/United States GR - UM1 AI100645/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20240122 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Peptides) RN - 0 (Peptide Library) SB - IM MH - Humans MH - Female MH - *Peptides/genetics MH - *Uterine Cervical Neoplasms/genetics MH - Amino Acid Sequence MH - Peptide Library MH - Benchmarking PMC - PMC10803737 COIS- NT is or has been a paid consultant Roche Pharma, Grey Wolf Therapeutics, T-Cypher Bio, Infinitopes, and Enara Bio. The remaining authors declare no competing interests. EDAT- 2024/01/23 00:42 MHDA- 2024/01/24 06:42 PMCR- 2024/01/22 CRDT- 2024/01/22 23:37 PHST- 2022/07/24 00:00 [received] PHST- 2023/12/14 00:00 [accepted] PHST- 2024/01/24 06:42 [medline] PHST- 2024/01/23 00:42 [pubmed] PHST- 2024/01/22 23:37 [entrez] PHST- 2024/01/22 00:00 [pmc-release] AID - 10.1038/s41467-023-44460-z [pii] AID - 44460 [pii] AID - 10.1038/s41467-023-44460-z [doi] PST - epublish SO - Nat Commun. 2024 Jan 22;15(1):661. doi: 10.1038/s41467-023-44460-z.