Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.
Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.
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靶向ATAD3A-PINK1-噬轴轴通过将PD-L1重定向到线粒体来克服化学免疫疗法的抗性。
DOI：
10.1038/s41422-022-00766-z
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发表时间：
2023-03
期刊：
影响因子：
44.1
通讯作者：
Bian, Xiu-Wu
中科院分区：
文献类型：
--
作者：
Xie, Xiao-Qing;Yang, Yi;Wang, Qiang;Liu, Hao-Fei;Fang, Xuan-Yu;Li, Cheng-Long;Jiang, Yi-Zhou;Wang, Shuai;Zhao, Hong-Yu;Miao, Jing-Ya;Ding, Shuai-Shuai;Liu, Xin-Dong;Yao, Xiao-Hong;Yang, Wen-Tao;Jiang, Jun;Shao, Zhi-Ming;Jin, Guoxiang;Bian, Xiu-Wu
只有一小部分三阴性乳腺癌患者受益于靶向PD-1/PD-L1信号传导的免疫检查点抑制剂（ICI）联合化疗。在这里，我们发现ICI加紫杉醇的治疗反应与PD-L1的亚细胞再分布有关。在我们的ICI联合白蛋白结合型紫杉醇的免疫治疗队列中，来自应答者的肿瘤样品显示PD-L1在线粒体上的显著分布，而非应答者显示PD-L1在肿瘤细胞膜而不是线粒体上的积累增加。我们的研究结果还表明，PD-L1的分布模式是由ATAD 3A-PINK 1轴调节的。从机制上讲，PINK 1通过线粒体自噬途径将PD-L1募集到线粒体中进行降解。重要的是，紫杉醇增加ATAD 3A表达，通过抑制PINK 1依赖性线粒体自噬来破坏PD-L1的蛋白稳态。临床上，在ICI联合紫杉醇治疗前检测到ATAD 3A高表达的肿瘤患者与ATAD 3A低表达肿瘤患者相比，无进展生存期明显缩短。临床前结果进一步证明，靶向ATAD 3A重置了有利的抗肿瘤免疫微环境，并增加了ICI加紫杉醇联合治疗的疗效。总之，我们的研究结果表明，ATAD 3A不仅通过阻止PD-L1线粒体分布作为ICI+紫杉醇联合治疗的耐药因子，而且还作为增加对化学免疫治疗的治疗反应的有希望的靶点。
Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.
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影响因子：
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作者：
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通讯作者：
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44.1
作者：
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