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

Simon J. Dovedi, Amy L. Adlard, Grazyna Lipowska-Bhalla, Conor McKenna, Sherrie Jones, Eleanor J. Cheadle, Ian J. Stratford, Edmund Poon, Michelle Morrow, Ross Stewart, Hazel Jones, Robert W. Wilkinson, Jamie Honeychurch, Tim M. Illidge

    Research output: Contribution to journalArticlepeer-review


    © 2014 American Association for Cancer Research.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.
    Original languageEnglish
    Pages (from-to)5458-5468
    Number of pages10
    JournalCancer Research
    Issue number19
    Publication statusPublished - 1 Oct 2014


    • Radiotherapy PD-L1 Immunotherapy Cancer


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