DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

被引：1351

作者：

Vanpouille-Box, Claire ^{[1
]}

Alard, Amandine ^{[2
,6
]}

Aryankalayil, Molykutty J. ^{[3
,4
]}

Sarfraz, Yasmeen ^{[1
]}

Diamond, Julie M. ^{[1
]}

Schneider, Robert J. ^{[2
]}

Inghirami, Giorgio ^{[5
]}

Coleman, C. Norman ^{[3
,4
]}

Formenti, Silvia C. ^{[1
]}

Demaria, Sandra ^{[1
,5
]}

机构：

[1] Weill Cornell Med, Dept Radiat Oncol, 1300 York Ave,Box 169, New York, NY 10065 USA

[2] NYU, Sch Med, Dept Microbiol, 450 29th St, New York, NY 10016 USA

[3] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3 B406,9000 Rockville Pike, Bethesda, MD 20892 USA

[4] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, Bldg 10,Room B3 B406,9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Weill Cornell Med, Dept Pathol & Lab Med, 525 East 68th St, New York, NY 10065 USA

[6] Univ Toulouse III Paul Sabatier, CRCT, Tumor Biol Dept, INSERM UMR 1037, F-31062 Toulouse, France

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

GMP-AMP SYNTHASE; LOCAL RADIATION-THERAPY; CELL LUNG-CANCER; ANTITUMOR IMMUNITY; T-CELLS; AUTOIMMUNE-DISEASE; DENDRITIC CELLS; BREAST-CANCER; MELANOMA; PATHWAY;

D O I：

10.1038/ncomms15618

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-beta by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-b production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8(+) T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.

引用

页数：15

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