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Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade

放射治疗 背向效应 医学 T细胞 癌症研究 肿瘤微环境 免疫原性 联合疗法 免疫系统 免疫疗法 流式细胞术 免疫学 内科学
作者
Simon J. Dovedi,Eleanor J. Cheadle,Amy L. Popple,Edmund Poon,Michelle Morrow,Ross Stewart,Erik Yusko,Catherine Sanders,Marissa Vignali,Ryan Emerson,Harlan Robins,Robert W. Wilkinson,Jamie Honeychurch,Tim Illidge
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:23 (18): 5514-5526 被引量:306
标识
DOI:10.1158/1078-0432.ccr-16-1673
摘要

Abstract Purpose: Radiotherapy is a highly effective anticancer 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. Radiotherapy is known to enhance tumor immunogenicity; however, the contribution and mechanisms of radiotherapy-induced immune responses are unknown. Experimental Design: The impact of low-dose fractionated radiotherapy (5 × 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing of the T-cell receptor (TCR) repertoire. A dual-tumor model was used, with fractionated radiotherapy 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 radiotherapy leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of preexisting T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anticancer immunity following radiotherapy, 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 radiotherapy and infiltrating T cells. Conclusions: These data provide evidence that radiotherapy can enhance T-cell trafficking to locally treated tumor sites and augment preexisting anticancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy. Clin Cancer Res; 23(18); 5514–26. ©2017 AACR.
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