dc.contributor.author | Coelho, MA | |
dc.contributor.author | de Carné Trécesson, S | |
dc.contributor.author | Rana, S | |
dc.contributor.author | Zecchin, D | |
dc.contributor.author | Moore, C | |
dc.contributor.author | Molina-Arcas, M | |
dc.contributor.author | East, P | |
dc.contributor.author | Spencer-Dene, B | |
dc.contributor.author | Nye, E | |
dc.contributor.author | Barnouin, K | |
dc.contributor.author | Snijders, AP | |
dc.contributor.author | Lai, WS | |
dc.contributor.author | Blackshear, PJ | |
dc.contributor.author | Downward, J | |
dc.date.accessioned | 2017-11-22T14:03:33Z | |
dc.date.issued | 2017-12-12 | |
dc.identifier.citation | Immunity, 2017, 47 (6), pp. 1083 - 1099.e6 | |
dc.identifier.issn | 1074-7613 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/929 | |
dc.identifier.eissn | 1097-4180 | |
dc.identifier.doi | 10.1016/j.immuni.2017.11.016 | |
dc.description.abstract | The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers. | |
dc.format | Print-Electronic | |
dc.format.extent | 1083 - 1099.e6 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Epithelial Cells | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Lung Neoplasms | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | MAP Kinase Kinase Kinases | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.subject | RNA, Messenger | |
dc.subject | Neoplasm Transplantation | |
dc.subject | Signal Transduction | |
dc.subject | Tumor Escape | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Protein Binding | |
dc.subject | RNA Stability | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Tristetraprolin | |
dc.subject | RNA Cleavage | |
dc.subject | B7-H1 Antigen | |
dc.title | Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-11-20 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1016/j.immuni.2017.11.016 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-12-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Immunity | |
pubs.issue | 6 | |
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/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
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/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
pubs.publication-status | Published | |
pubs.volume | 47 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |