粒体自噬
化学免疫疗法
品脱1
癌症研究
紫杉醇
生物
DNM1L型
线粒体
联合疗法
免疫疗法
药理学
自噬
癌症
免疫系统
免疫学
细胞凋亡
细胞生物学
生物化学
遗传学
线粒体分裂
作者
Xiaoqing Xie,Yi Yang,Qiang Wang,Hao-Fei Liu,Xuanyu Fang,Chenglong Li,Yi‐Zhou Jiang,Shuai Wang,Hongyu Zhao,Jingya Miao,Shuaishuai Ding,Xindong Liu,Xiaohong Yao,Wentao Yang,Jun Jiang,Zhi-Ming Shao,Guoxiang Jin,Xiu‐Wu Bian
出处
期刊:Cell Research
[Springer Nature]
日期:2023-01-10
卷期号:33 (3): 215-228
被引量:13
标识
DOI:10.1038/s41422-022-00766-z
摘要
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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