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dc.contributor.authorPatin, ECen_US
dc.contributor.authorDillon, MTen_US
dc.contributor.authorNenclares, Pen_US
dc.contributor.authorGrove, Len_US
dc.contributor.authorSoliman, Hen_US
dc.contributor.authorLeslie, Ien_US
dc.contributor.authorNorthcote, Den_US
dc.contributor.authorBozhanova, Gen_US
dc.contributor.authorCrespo-Rodriguez, Een_US
dc.contributor.authorBaldock, Hen_US
dc.contributor.authorWhittock, Hen_US
dc.contributor.authorBaker, Gen_US
dc.contributor.authorKyula, Jen_US
dc.contributor.authorGuevara, Jen_US
dc.contributor.authorMelcher, AAen_US
dc.contributor.authorHarper, Jen_US
dc.contributor.authorGhadially, Hen_US
dc.contributor.authorSmith, Sen_US
dc.contributor.authorPedersen, Men_US
dc.contributor.authorMcLaughlin, Men_US
dc.contributor.authorHarrington, KJen_US
dc.date.accessioned2022-05-25T13:25:07Z
dc.date.available2022-05-25T13:25:07Z
dc.date.issued2022-03en_US
dc.identifier.citationJournal for immunotherapy of cancer, 2022, 10 (3)en_US
dc.identifier.issn2051-1426en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5146
dc.identifier.eissn2051-1426en_US
dc.identifier.doi10.1136/jitc-2021-004306en_US
dc.description.abstract<h4>Background</h4>Despite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.<h4>Methods</h4>Using the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.<h4>Results</h4>ATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.<h4>Conclusion</h4>This work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage-response inhibitors and immune checkpoint blockade.en_US
dc.formatPrinten_US
dc.languageengen_US
dc.language.isoengen_US
dc.titleHarnessing radiotherapy-induced NK-cell activity by combining DNA damage-response inhibition and immune checkpoint blockade.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-02-06en_US
rioxxterms.versionofrecord10.1136/jitc-2021-004306en_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/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/14/15 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/20/21 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume10en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTargeted Therapy
dc.contributor.icrauthorMcLaughlin, Martinen_US
dc.contributor.icrauthorHarrington, Kevinen_US
dc.contributor.icrauthorPedersen, Malinen_US
dc.contributor.icrauthorDillon, Magnusen_US
dc.contributor.icrauthorPatin, Emmanuelen_US
dc.contributor.icrauthorNenclares, Pabloen_US


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