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dc.contributor.authorDillon, MT
dc.contributor.authorBergerhoff, KF
dc.contributor.authorPedersen, M
dc.contributor.authorWhittock, H
dc.contributor.authorCrespo-Rodriguez, E
dc.contributor.authorPatin, EC
dc.contributor.authorPearson, A
dc.contributor.authorSmith, HG
dc.contributor.authorPaget, JTE
dc.contributor.authorPatel, RR
dc.contributor.authorFoo, S
dc.contributor.authorBozhanova, G
dc.contributor.authorRagulan, C
dc.contributor.authorFontana, E
dc.contributor.authorDesai, K
dc.contributor.authorWilkins, AC
dc.contributor.authorSadanandam, A
dc.contributor.authorMelcher, A
dc.contributor.authorMcLaughlin, M
dc.contributor.authorHarrington, KJ
dc.date.accessioned2019-01-29T14:10:30Z
dc.date.issued2019-06
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (11), pp. 3392 - 3403
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3034
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-18-1821
dc.description.abstractPurpose ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment. Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy.Results Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3 + and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found in vivo , with in vitro data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT.Conclusions We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid-sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity.
dc.formatPrint-Electronic
dc.format.extent3392 - 3403
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectLymphocytes, Tumor-Infiltrating
dc.subjectCell Line, Tumor
dc.subjectMyeloid Cells
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectNeoplasms
dc.subjectDisease Models, Animal
dc.subjectCytokines
dc.subjectProtein Kinase Inhibitors
dc.subjectXenograft Model Antitumor Assays
dc.subjectRadiation, Ionizing
dc.subjectTumor Microenvironment
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.titleATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment.
dc.typeJournal Article
dcterms.dateAccepted2019-02-11
rioxxterms.versionofrecord10.1158/1078-0432.ccr-18-1821
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue11
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
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
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/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
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.publication-statusPublished
pubs.volume25
pubs.embargo.termsNot known
icr.researchteamSystems and Precision Cancer Medicineen_US
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorBozhanova, Galabinaen
dc.contributor.icrauthorWilkins, Annaen
dc.contributor.icrauthorDillon, Magnusen
dc.contributor.icrauthorFontana, Elisaen
dc.contributor.icrauthorSadanandam, Angurajen
dc.contributor.icrauthorMelcher, Alanen
dc.contributor.icrauthorHarrington, Kevinen
dc.contributor.icrauthorSmith, Henryen
dc.contributor.icrauthorMcLaughlin, Martinen
dc.contributor.icrauthorPedersen, Malinen


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