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    Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade.

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    Authors
    Dovedi, Simon J
    Adlard, A
    Lipowska-Bhalla, Grazyna
    McKenna, Conor
    Jones, Sherrie
    Cheadle, Eleanor J
    Stratford, I
    Poon, E
    Morrow, M
    Stewart, R
    Jones, H
    Wilkinson, R
    Honeychurch, Jamie
    Illidge, Timothy M
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    Affiliation
    Targeted 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.
    Issue Date
    2014-10-01
    
    Metadata
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    Abstract
    Radiotherapy 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.
    Citation
    Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. 2014, 74 (19):5458-68 Cancer Res
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/336221
    DOI
    10.1158/0008-5472.CAN-14-1258
    PubMed ID
    25274032
    Type
    Article
    Language
    en
    ISSN
    1538-7445
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-14-1258
    Scopus Count
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    All Paterson Institute for Cancer Research

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