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dc.contributor.authorBozhanova, Gen_US
dc.contributor.authorHassan, Jen_US
dc.contributor.authorAppleton, Len_US
dc.contributor.authorJennings, Ven_US
dc.contributor.authorFoo, Sen_US
dc.contributor.authorMcLaughlin, Men_US
dc.contributor.authorChan Wah Hak, CMen_US
dc.contributor.authorPatin, ECen_US
dc.contributor.authorCrespo-Rodriguez, Een_US
dc.contributor.authorBaker, Gen_US
dc.contributor.authorArmstrong, Een_US
dc.contributor.authorChiu, Men_US
dc.contributor.authorPandha, Hen_US
dc.contributor.authorSamson, Aen_US
dc.contributor.authorRoulstone, Ven_US
dc.contributor.authorKyula, Jen_US
dc.contributor.authorVile, Ren_US
dc.contributor.authorErrington-Mais, Fen_US
dc.contributor.authorPedersen, Men_US
dc.contributor.authorHarrington, Ken_US
dc.contributor.authorOno, Men_US
dc.contributor.authorMelcher, Aen_US
dc.date.accessioned2022-05-25T13:25:00Z
dc.date.available2022-05-25T13:25:00Z
dc.date.issued2022-03en_US
dc.identifier.citationJournal for immunotherapy of cancer, 2022, 10 (3), pp. e004410 - ?en_US
dc.identifier.issn2051-1426en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5144
dc.identifier.eissn2051-1426en_US
dc.identifier.doi10.1136/jitc-2021-004410en_US
dc.description.abstractCombination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI). Using a BRAFV600E-driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the 'Timer of Cell Kinetics and Activity' system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics. Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity. Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors.en_US
dc.formatPrinten_US
dc.format.extente004410 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectCD4-Positive T-Lymphocytesen_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectHerpes Simplexen_US
dc.subjectMelanomaen_US
dc.subjectProto-Oncogene Proteins B-rafen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectImmunityen_US
dc.subjectOncolytic Virusesen_US
dc.titleCD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-03-04en_US
rioxxterms.versionofrecord10.1136/jitc-2021-004410en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2022-03en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal for immunotherapy of canceren_US
pubs.issue3en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/ImmNet
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.volume10en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTargeted Therapy
icr.researchteamTranslational Immunotherapy
dc.contributor.icrauthorMcLaughlin, Martinen_US
dc.contributor.icrauthorHarrington, Kevinen_US
dc.contributor.icrauthorPedersen, Malinen_US
dc.contributor.icrauthorMelcher, Alanen_US


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