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dc.contributor.authorNewey, A
dc.contributor.authorGriffiths, B
dc.contributor.authorMichaux, J
dc.contributor.authorPak, HS
dc.contributor.authorStevenson, BJ
dc.contributor.authorWoolston, A
dc.contributor.authorSemiannikova, M
dc.contributor.authorSpain, G
dc.contributor.authorBarber, LJ
dc.contributor.authorMatthews, N
dc.contributor.authorRao, S
dc.contributor.authorWatkins, D
dc.contributor.authorChau, I
dc.contributor.authorCoukos, G
dc.contributor.authorRacle, J
dc.contributor.authorGfeller, D
dc.contributor.authorStarling, N
dc.contributor.authorCunningham, D
dc.contributor.authorBassani-Sternberg, M
dc.contributor.authorGerlinger, M
dc.date.accessioned2019-11-18T09:55:02Z
dc.date.issued2019-11-18
dc.identifier.citationJournal for immunotherapy of cancer, 2019, 7 (1), pp. 309 - ?
dc.identifier.issn2051-1426
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3420
dc.identifier.eissn2051-1426en_US
dc.identifier.doi10.1186/s40425-019-0769-8en_US
dc.description.abstractBackground Patient derived organoids (PDOs) can be established from colorectal cancers (CRCs) as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFNγ) or MEK-inhibitor treatment.Methods Four microsatellite stable PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analyzed by MS.Results We identified an average of 9936 unique peptides per PDO which compares favorably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. In contrast, computational HLA binding prediction estimated that 304 mutations could generate neoantigens. One hundred ninety-six of these were located in expressed genes, still exceeding the number of MS-detected neoantigens 65-fold. Treatment of four PDOs with IFNγ upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFNγ-inducible genes. HLA class II presented peptides increased dramatically with IFNγ treatment. MEK-inhibitor treatment showed no consistent effect on HLA class I or II expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment.Conclusions Only 3 out of 612 non-silent mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
dc.formatElectronic
dc.format.extent309 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectOrganoids
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectMAP Kinase Kinase Kinases
dc.subjectPeptides
dc.subjectAntigens, Neoplasm
dc.subjectHistocompatibility Antigens Class I
dc.subjectProtein Kinase Inhibitors
dc.subjectProteomics
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectInterferon-gamma
dc.titleImmunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment.
dc.typeJournal Article
dcterms.dateAccepted2019-10-02
rioxxterms.versionofrecord10.1186/s40425-019-0769-8
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-11-18en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal for immunotherapy of cancer
pubs.issue1
pubs.notes6 months
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublished
pubs.volume7en_US
pubs.embargo.terms6 months
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamTranslational Oncogenomicsen_US
dc.contributor.icrauthorNewey, Aliceen
dc.contributor.icrauthorSemiannikova, Mariaen
dc.contributor.icrauthorBarber, Louiseen
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorStarling, Naureenen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorGerlinger, Marcoen


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