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dc.contributor.authorEvgin, Len_US
dc.contributor.authorHuff, ALen_US
dc.contributor.authorKottke, Ten_US
dc.contributor.authorThompson, Jen_US
dc.contributor.authorMolan, AMen_US
dc.contributor.authorDriscoll, CBen_US
dc.contributor.authorSchuelke, Men_US
dc.contributor.authorShim, KGen_US
dc.contributor.authorWongthida, Pen_US
dc.contributor.authorIlett, EJen_US
dc.contributor.authorSmith, KKen_US
dc.contributor.authorHarris, RSen_US
dc.contributor.authorCoffey, Men_US
dc.contributor.authorPulido, JSen_US
dc.contributor.authorPandha, Hen_US
dc.contributor.authorSelby, PJen_US
dc.contributor.authorHarrington, KJen_US
dc.contributor.authorMelcher, Aen_US
dc.contributor.authorVile, RGen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-06-24T09:31:52Z
dc.date.issued2019-05en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30940643en_US
dc.identifier2326-6066.CIR-18-0013en_US
dc.identifier.citationCancer Immunol Res, 2019, 7 (5), pp. 828 - 840en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3273
dc.identifier.eissn2326-6074en_US
dc.identifier.doi10.1158/2326-6066.CIR-18-0013en_US
dc.description.abstractAntitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T-cell-mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a coapplied therapy (oncolytic or suicide gene therapy) was promoted. This T-cell-mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFα and protein kinase C-dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both in vitro and in vivo Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from first-line therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.en_US
dc.format.extent828 - 840en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleSuboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-03-27en_US
rioxxterms.versionofrecord10.1158/2326-6066.CIR-18-0013en_US
rioxxterms.licenseref.startdate2019-05en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCancer Immunol Resen_US
pubs.issue5en_US
pubs.notesNot knownen_US
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/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.publication-statusPublisheden_US
pubs.volume7en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorMelcher, Alanen_US
dc.contributor.icrauthorHarrington, Kevinen_US


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