dc.contributor.author | Chabanon, RM | |
dc.contributor.author | Muirhead, G | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Adam, J | |
dc.contributor.author | Morel, D | |
dc.contributor.author | Garrido, M | |
dc.contributor.author | Lamb, A | |
dc.contributor.author | Hénon, C | |
dc.contributor.author | Dorvault, N | |
dc.contributor.author | Rouanne, M | |
dc.contributor.author | Marlow, R | |
dc.contributor.author | Bajrami, I | |
dc.contributor.author | Cardeñosa, ML | |
dc.contributor.author | Konde, A | |
dc.contributor.author | Besse, B | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Marabelle, A | |
dc.contributor.author | Tutt, AN | |
dc.contributor.author | Soria, J-C | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Postel-Vinay, S | |
dc.date.accessioned | 2020-06-09T11:59:39Z | |
dc.date.issued | 2019-03-01 | |
dc.identifier.citation | The Journal of clinical investigation, 2019, 129 (3), pp. 1211 - 1228 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3708 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/jci123319 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 1211 - 1228 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lung Neoplasms | |
dc.subject | Endonucleases | |
dc.subject | Nucleotidyltransferases | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Membrane Proteins | |
dc.subject | BRCA1 Protein | |
dc.subject | Female | |
dc.subject | Interferon-gamma | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Poly (ADP-Ribose) Polymerase-1 | |
dc.subject | A549 Cells | |
dc.subject | B7-H1 Antigen | |
dc.title | PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-12-18 | |
rioxxterms.versionofrecord | 10.1172/jci123319 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-03 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of clinical investigation | |
pubs.issue | 3 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 129 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Haider, Syed | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Lord, Christopher | |