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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.
Nature Communications ( IF 14.7 ) Pub Date : 2017-06-09 , DOI: 10.1038/ncomms15618 Claire Vanpouille-Box 1 , Amandine Alard 2, 3 , Molykutty J Aryankalayil 4 , Yasmeen Sarfraz 1 , Julie M Diamond 1 , Robert J Schneider 2 , Giorgio Inghirami 5 , C Norman Coleman 4 , Silvia C Formenti 1 , Sandra Demaria 1, 5
Nature Communications ( IF 14.7 ) Pub Date : 2017-06-09 , DOI: 10.1038/ncomms15618 Claire Vanpouille-Box 1 , Amandine Alard 2, 3 , Molykutty J Aryankalayil 4 , Yasmeen Sarfraz 1 , Julie M Diamond 1 , Robert J Schneider 2 , Giorgio Inghirami 5 , C Norman Coleman 4 , Silvia C Formenti 1 , Sandra Demaria 1, 5
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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-β 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-β 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.
中文翻译：
DNA核酸外切酶Trex1调节放疗诱导的肿瘤免疫原性。
放射疗法具有增强对免疫疗法反应的能力，目前正在研究中。然而，辐射诱导抗肿瘤T细胞的机制仍不清楚。我们表明，DNA核酸外切酶Trex1是由不同癌细胞中高于12-18 Gy的辐射剂量诱导的，并且通过降解辐射时累积在细胞质中的DNA来减弱其免疫原性。在激活DNA传感器cGAS及其下游效应器STING之后，胞质DNA刺激癌细胞分泌干扰素-β。以不诱导Trex1的剂量重复照射会放大干扰素-β的产生，从而导致Batf3依赖性树突状细胞的募集和激活。此效应对于启动CD8 +是必不可少的在免疫检查点封锁的情况下介导全身性肿瘤排斥（绝对作用）的T细胞。因此，Trex1是辐射驱动的抗肿瘤免疫力的上游调节剂。Trex1诱导可能指导接受免疫治疗的患者的辐射剂量和分级选择。
更新日期：2017-06-12
中文翻译：
DNA核酸外切酶Trex1调节放疗诱导的肿瘤免疫原性。
放射疗法具有增强对免疫疗法反应的能力，目前正在研究中。然而，辐射诱导抗肿瘤T细胞的机制仍不清楚。我们表明，DNA核酸外切酶Trex1是由不同癌细胞中高于12-18 Gy的辐射剂量诱导的，并且通过降解辐射时累积在细胞质中的DNA来减弱其免疫原性。在激活DNA传感器cGAS及其下游效应器STING之后，胞质DNA刺激癌细胞分泌干扰素-β。以不诱导Trex1的剂量重复照射会放大干扰素-β的产生，从而导致Batf3依赖性树突状细胞的募集和激活。此效应对于启动CD8 +是必不可少的在免疫检查点封锁的情况下介导全身性肿瘤排斥（绝对作用）的T细胞。因此，Trex1是辐射驱动的抗肿瘤免疫力的上游调节剂。Trex1诱导可能指导接受免疫治疗的患者的辐射剂量和分级选择。
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