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

Autor:	Dovedi SJ; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, United Kingdom. DovediSi@MedImmune.com Tim.Illidge@manchester.ac.uk.; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Cheadle EJ; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, United Kingdom., Popple AL; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, United Kingdom., Poon E; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Morrow M; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Stewart R; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Yusko EC; Adaptive Biotechnologies, Seattle, Washington., Sanders CM; Adaptive Biotechnologies, Seattle, Washington., Vignali M; Adaptive Biotechnologies, Seattle, Washington., Emerson RO; Adaptive Biotechnologies, Seattle, Washington., Robins HS; Fred Hutchinson Cancer Research Center, Seattle, Washington., Wilkinson RW; MedImmune Ltd., Granta Park, Cambridge, United Kingdom., Honeychurch J; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, United Kingdom., Illidge TM; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Christie Hospital, Manchester Academic Health Sciences Centre, United Kingdom. DovediSi@MedImmune.com Tim.Illidge@manchester.ac.uk.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Sep 15; Vol. 23 (18), pp. 5514-5526. Date of Electronic Publication: 2017 May 22.
DOI:	10.1158/1078-0432.CCR-16-1673
Abstrakt:	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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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