RT Journal Article
SR Electronic
T1 Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e003404
DO 10.1136/jitc-2021-003404
VO 9
IS 10
A1 Ana Marcu
A1 Andreas Schlosser
A1 Anne Keupp
A1 Nico Trautwein
A1 Pascal Johann
A1 Matthias Wölfl
A1 Johanna Lager
A1 Camelia Maria Monoranu
A1 Juliane S Walz
A1 Lisa M Henkel
A1 Jürgen Krauß
A1 Martin Ebinger
A1 Martin Schuhmann
A1 Ulrich Wilhelm Thomale
A1 Torsten Pietsch
A1 Erdwine Klinker
A1 Paul G Schlegel
A1 Florian Oyen
A1 Yair Reisner
A1 Hans-Georg Rammensee
A1 Matthias Eyrich
YR 2021
UL http://jitc.bmj.com/content/9/10/e003404.abstract
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.Data are available in a public, open access repository. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository (doi: 10.1093/nar/gky1106).