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000172542 1001_ $$aMarcu, Ana$$b0
000172542 245__ $$aNatural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.
000172542 260__ $$aLondon$$bBioMed Central$$c2021
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000172542 520__ $$aAtypical 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.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.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.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.
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000172542 650_7 $$2Other$$aantigens
000172542 650_7 $$2Other$$aepitope mapping
000172542 650_7 $$2Other$$aimmunotherapy
000172542 650_7 $$2Other$$aneoplasm
000172542 650_7 $$2Other$$apediatrics
000172542 650_7 $$2Other$$avaccination
000172542 7001_ $$aSchlosser, Andreas$$b1
000172542 7001_ $$aKeupp, Anne$$b2
000172542 7001_ $$aTrautwein, Nico$$b3
000172542 7001_ $$0P:(DE-He78)3fdc3623477264cb5d0e14f256dbfbb8$$aJohann, Pascal$$b4$$udkfz
000172542 7001_ $$aWölfl, Matthias$$b5
000172542 7001_ $$aLager, Johanna$$b6
000172542 7001_ $$aMonoranu, Camelia Maria$$b7
000172542 7001_ $$0P:(DE-HGF)0$$aWalz, Juliane S$$b8
000172542 7001_ $$aHenkel, Lisa M$$b9
000172542 7001_ $$aKrauß, Jürgen$$b10
000172542 7001_ $$aEbinger, Martin$$b11
000172542 7001_ $$aSchuhmann, Martin$$b12
000172542 7001_ $$aThomale, Ulrich Wilhelm$$b13
000172542 7001_ $$aPietsch, Torsten$$b14
000172542 7001_ $$aKlinker, Erdwine$$b15
000172542 7001_ $$aSchlegel, Paul G$$b16
000172542 7001_ $$aOyen, Florian$$b17
000172542 7001_ $$aReisner, Yair$$b18
000172542 7001_ $$aRammensee, Hans-Georg$$b19
000172542 7001_ $$00000-0002-8099-5903$$aEyrich, Matthias$$b20
000172542 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2021-003404$$gVol. 9, no. 10, p. e003404 -$$n10$$pe003404 $$tJournal for ImmunoTherapy of Cancer$$v9$$x2051-1426$$y2021
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