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    Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade.

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    Authors
    Dovedi, S
    Cheadle, Eleanor J
    Popple, Amy
    Poon, E
    Morrow, M
    Stewart, R
    Yusko, E
    Sanders, C
    Vignali, M
    Emerson, R
    Robins, H
    Wilkinson, R
    Honeychurch, Jamie
    Illidge, Timothy M
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    Affiliation
    Oncology Research, MedImmune Ltd
    Issue Date
    2017-05-22
    
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    Abstract
    Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown. Experimental Design: The impact of low-dose fractionated RT (5 x 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing (NGS) of the T-cell receptor (TCR)-repertoire. A dual-tumor model was used, with fractionated RT delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field. Results: We show that fractionated RT leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of pre-existing T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anti-cancer immunity following RT which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T-cells resident in the tumor at the time of RT and infiltrating T-cells. Conclusions: These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.
    Citation
    Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade. 2017 Clin Cancer Res
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/620422
    DOI
    10.1158/1078-0432.CCR-16-1673
    PubMed ID
    28533222
    Type
    Article
    Language
    en
    ISSN
    1078-0432
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.CCR-16-1673
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