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

Simon Dovedi, Eleanor Cheadle, Amy Lee Popple, Edmund Poon, Michelle Morrow, Ross Stewart, Erik C. Yusko, Catherine M. Sanders, Marissa Vignali, Ryan O. Emerson, Harlan S. Robins, Robert W. Wilkinson, Jamie Honeychurch, Timothy Illidge

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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. <p>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.</p> <p>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.</p> <p>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.
Original languageEnglish
Pages (from-to)5514–5526
JournalClinical Cancer Research
Volume23
Issue number18
DOIs
Publication statusPublished - 22 May 2017

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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