PMID- 34599019 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20220111 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 10 DP - 2021 Oct TI - Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors. LID - 10.1136/jitc-2021-003404 [doi] LID - e003404 AB - BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8(+) T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Marcu, Ana AU - Marcu A AD - Institute for Cell Biology, Department of Immunology, University of Tubingen, Tubingen, Germany. FAU - Schlosser, Andreas AU - Schlosser A AD - Rudolf-Virchow Zentrum, University Wurzburg, Wurzburg, Germany. FAU - Keupp, Anne AU - Keupp A AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Trautwein, Nico AU - Trautwein N AD - Institute for Cell Biology, Department of Immunology, University of Tubingen, Tubingen, Germany. FAU - Johann, Pascal AU - Johann P AD - Swabian Children's Cancer Center, Augsburg, Germany. AD - DKFZ Heidelberg, Heidelberg, Germany. FAU - Wolfl, Matthias AU - Wolfl M AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Lager, Johanna AU - Lager J AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Monoranu, Camelia Maria AU - Monoranu CM AD - Department of Neuropathology, Institute for Pathology, University of Wurzburg, Wurzburg, Germany. FAU - Walz, Juliane S AU - Walz JS AD - Institute for Cell Biology, Department of Immunology, University of Tubingen, Tubingen, Germany. AD - Cluster of Excellence iFIT (EXC2180), University of Tubingen, Tubingen, Germany. AD - Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and Robert Bosch Center for Tumor Diseases (RBCT), Stuttgart, Germany. AD - Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital of Tubingen, Tubingen, Germany. FAU - Henkel, Lisa M AU - Henkel LM AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Krauss, Jurgen AU - Krauss J AD - Department of Neurosurgery, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Ebinger, Martin AU - Ebinger M AD - University Children's Hospital, University Medical Center Tubingen, Tubingen, Germany. FAU - Schuhmann, Martin AU - Schuhmann M AD - Department of Neurosurgery, University Medical Center Tubingen, Tubingen, Germany. FAU - Thomale, Ulrich Wilhelm AU - Thomale UW AD - Department of Neurosurgery, Charite, Berlin, Germany. FAU - Pietsch, Torsten AU - Pietsch T AD - Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, Bonn, Germany. FAU - Klinker, Erdwine AU - Klinker E AD - Institute for Transfusion Medicine, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Schlegel, Paul G AU - Schlegel PG AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany. FAU - Oyen, Florian AU - Oyen F AD - University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Reisner, Yair AU - Reisner Y AD - Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. FAU - Rammensee, Hans-Georg AU - Rammensee HG AD - Institute for Cell Biology, Department of Immunology, University of Tubingen, Tubingen, Germany. FAU - Eyrich, Matthias AU - Eyrich M AUID- ORCID: 0000-0002-8099-5903 AD - University Children's Hospital, University Medical Center Wurzburg, Wurzburg, Germany eyrich_m@ukw.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (HLA Antigens) RN - 0 (Peptides) RN - 0 (Peptides, Cyclic) SB - IM MH - Adolescent MH - Central Nervous System Neoplasms/genetics/*immunology/metabolism/therapy MH - Child MH - Child, Preschool MH - Female MH - HLA Antigens/genetics/immunology/metabolism MH - Humans MH - Immunohistochemistry MH - Immunotherapy MH - Male MH - Mass Spectrometry MH - Oncogenes MH - Peptides/*immunology/metabolism MH - Peptides, Cyclic MH - Rhabdoid Tumor/genetics/*immunology/metabolism/therapy PMC - PMC8488729 OTO - NOTNLM OT - antigens OT - epitope mapping OT - immunotherapy OT - neoplasm OT - pediatrics OT - vaccination COIS- Competing interests: MEy has taken part in pediatric advisory boards of BMS and Atara Biotherapeutics and holds research collaborations with CellSource and Miltenyi Biotec. EDAT- 2021/10/03 06:00 MHDA- 2022/01/12 06:00 PMCR- 2021/10/01 CRDT- 2021/10/02 05:34 PHST- 2021/08/26 00:00 [accepted] PHST- 2021/10/02 05:34 [entrez] PHST- 2021/10/03 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/10/01 00:00 [pmc-release] AID - jitc-2021-003404 [pii] AID - 10.1136/jitc-2021-003404 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Oct;9(10):e003404. doi: 10.1136/jitc-2021-003404.