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dc.contributor.authorChabanon, RM
dc.contributor.authorMuirhead, G
dc.contributor.authorKrastev, DB
dc.contributor.authorAdam, J
dc.contributor.authorMorel, D
dc.contributor.authorGarrido, M
dc.contributor.authorLamb, A
dc.contributor.authorHénon, C
dc.contributor.authorDorvault, N
dc.contributor.authorRouanne, M
dc.contributor.authorMarlow, R
dc.contributor.authorBajrami, I
dc.contributor.authorCardeñosa, ML
dc.contributor.authorKonde, A
dc.contributor.authorBesse, B
dc.contributor.authorAshworth, A
dc.contributor.authorPettitt, SJ
dc.contributor.authorHaider, S
dc.contributor.authorMarabelle, A
dc.contributor.authorTutt, AN
dc.contributor.authorSoria, J-C
dc.contributor.authorLord, CJ
dc.contributor.authorPostel-Vinay, S
dc.date.accessioned2020-06-09T11:59:39Z
dc.date.issued2019-03
dc.identifier.citationThe Journal of clinical investigation, 2019, 129 (3), pp. 1211 - 1228
dc.identifier.issn0021-9738
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3708
dc.identifier.eissn1558-8238
dc.identifier.doi10.1172/jci123319
dc.description.abstractThe cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.
dc.formatPrint-Electronic
dc.format.extent1211 - 1228
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectCarcinoma, Non-Small-Cell Lung
dc.subjectLung Neoplasms
dc.subjectEndonucleases
dc.subjectNucleotidyltransferases
dc.subjectDNA-Binding Proteins
dc.subjectMembrane Proteins
dc.subjectBRCA1 Protein
dc.subjectFemale
dc.subjectInterferon-gamma
dc.subjectTriple Negative Breast Neoplasms
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectPoly (ADP-Ribose) Polymerase-1
dc.subjectA549 Cells
dc.subjectB7-H1 Antigen
dc.titlePARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-12-18
rioxxterms.versionofrecord10.1172/jci123319
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of clinical investigation
pubs.issue3
pubs.notesNot known
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume129
pubs.embargo.termsNot known
icr.researchteamGene Functionen_US
dc.contributor.icrauthorHaider, Syeden
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorTutt, Andrewen
dc.contributor.icrauthorKrastev, Dragomiren


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