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dc.contributor.authorDovedi, Simon J*
dc.contributor.authorAdlard, A*
dc.contributor.authorLipowska-Bhalla, Grazyna*
dc.contributor.authorMcKenna, Conor*
dc.contributor.authorJones, Sherrie*
dc.contributor.authorCheadle, Eleanor J*
dc.contributor.authorStratford, I*
dc.contributor.authorPoon, E*
dc.contributor.authorMorrow, M*
dc.contributor.authorStewart, R*
dc.contributor.authorJones, H*
dc.contributor.authorWilkinson, R*
dc.contributor.authorHoneychurch, Jamie*
dc.contributor.authorIllidge, Timothy M*
dc.date.accessioned2014-11-27T09:54:57Z
dc.date.available2014-11-27T09:54:57Z
dc.date.issued2014-10-01
dc.identifier.citationAcquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. 2014, 74 (19):5458-68 Cancer Resen
dc.identifier.issn1538-7445
dc.identifier.pmid25274032
dc.identifier.doi10.1158/0008-5472.CAN-14-1258
dc.identifier.urihttp://hdl.handle.net/10541/336221
dc.description.abstractRadiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.
dc.language.isoenen
dc.rightsArchived with thanks to Cancer researchen
dc.titleAcquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.en
dc.typeArticleen
dc.contributor.departmentTargeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom. Simon.Dovedi@ics.manchester.ac.uk.en
dc.identifier.journalCancer Researchen
dc.description.collectionLymphoma Research Teamen
html.description.abstractRadiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8(+) T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen-specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8(+) T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti-PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes.


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