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自噬抑制线粒体DNA对辐射的反应
作者:小柯机器人 发布时间:2020/8/4 21:21:13

美国桑德拉和爱德华·迈耶癌症中心Lorenzo Galluzzi研究团队近日取得一项新成果。他们发现线粒体DNA通过abscopal反应应对辐射,而自噬抑制该反应。相关论文于2020年8月3日发表在《自然—免疫学》杂志上。

必需自噬基因的缺失增加了小鼠乳腺癌细胞对体外和体内放射免疫的敏感性(在具有免疫能力的同系宿主中)。自噬缺陷细胞分泌的I型干扰素(IFN)增加,这种增加可以通过CGAS或STING敲低、线粒体DNA耗竭、BCL2过表达或BAX缺失阻碍线粒体外膜通透性而逆转。

在体内,对自噬能力缺陷乳腺肿瘤细胞进行放射可产生强烈的免疫反应,从而通过全身性I型IFN信号传导改善对远距离非放射病灶的控制。最后,自噬的遗传特征与乳腺癌患者的预后成负相关,相反,与线粒体丰度、I型干扰素信号传导和效应因子免疫相关。

由于缺乏临床上可用的自噬抑制剂,该研究表明线粒体外膜通透性可能作为增强乳腺癌患者放疗免疫原性的有效靶标。

据悉,自噬维持细胞和生物体的内稳态。然而,尚不清楚癌症治疗过程中是否应抑制或激活自噬。

附:英文原文

Title: Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy

Author: Takahiro Yamazaki, Alexander Kirchmair, Ai Sato, Aitziber Buqu, Marissa Rybstein, Giulia Petroni, Norma Bloy, Francesca Finotello, Lena Stafford, Esther Navarro Manzano, Francisco Ayala de la Pea, Elena Garca-Martnez, Silvia C. Formenti, Zlatko Trajanoski, Lorenzo Galluzzi

Issue&Volume: 2020-08-03

Abstract: Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer. Autophagy controls cellular homeostasis and influences immune responses. Galluzzi and colleagues show that tumor cell autophagy opposes inflammatory cell death following radiation therapy and can be inhibited to enhance antitumor responses.

DOI: 10.1038/s41590-020-0751-0

Source: https://www.nature.com/articles/s41590-020-0751-0

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex