Show simple item record

dc.contributor.authorRoux, C
dc.contributor.authorJafari, SM
dc.contributor.authorShinde, R
dc.contributor.authorDuncan, G
dc.contributor.authorCescon, DW
dc.contributor.authorSilvester, J
dc.contributor.authorChu, MF
dc.contributor.authorHodgson, K
dc.contributor.authorBerger, T
dc.contributor.authorWakeham, A
dc.contributor.authorPalomero, L
dc.contributor.authorGarcia-Valero, M
dc.contributor.authorPujana, MA
dc.contributor.authorMak, TW
dc.contributor.authorMcGaha, TL
dc.contributor.authorCappello, P
dc.contributor.authorGorrini, C
dc.date.accessioned2020-09-30T11:05:04Z
dc.date.issued2019-03-05
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2019, 116 (10), pp. 4326 - 4335
dc.identifier.issn0027-8424
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4094
dc.identifier.eissn1091-6490
dc.identifier.doi10.1073/pnas.1819473116
dc.description.abstractThe combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.
dc.formatPrint-Electronic
dc.format.extent4326 - 4335
dc.languageeng
dc.language.isoeng
dc.publisherNATL ACAD SCIENCES
dc.subjectCell Line, Tumor
dc.subjectMacrophages
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectReactive Oxygen Species
dc.subjectPaclitaxel
dc.subjectButhionine Sulfoximine
dc.subjectGlutathione
dc.subjectRNA, Messenger
dc.subjectChemokines
dc.subjectImmunosuppressive Agents
dc.subjectDrug Therapy
dc.subjectUp-Regulation
dc.subjectPhenotype
dc.subjectFemale
dc.subjectTumor Microenvironment
dc.subjectTriple Negative Breast Neoplasms
dc.subjectB7-H1 Antigen
dc.titleReactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1.
dc.typeJournal Article
rioxxterms.versionofrecord10.1073/pnas.1819473116
rioxxterms.licenseref.startdate2019-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfProceedings of the National Academy of Sciences of the United States of America
pubs.issue10
pubs.notesNo embargo
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublished
pubs.volume116
pubs.embargo.termsNo embargo
icr.researchteamTarget Evaluation and Molecular Therapeutics
dc.contributor.icrauthorGorrini, Chiara


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record