Volume 33, No 3, Mar 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 3, March 2023: 215-228   |  Open Access

ORIGINAL ARTICLES

Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

Xiao-Qing Xie¹ , Yi Yang¹ , Qiang Wang^1,2 , Hao-Fei Liu¹ , Xuan-Yu Fang¹ , Cheng-Long Li¹ , Yi-Zhou Jiang³ , Shuai Wang¹ , Hong-Yu Zhao^4,5 , Jing-Ya Miao¹ , Shuai-Shuai Ding¹ , Xin-Dong Liu¹ , Xiao-Hong Yao¹ , Wen-Tao Yang⁶ , Jun Jiang⁷ , Zhi-Ming Shao³ , Guoxiang Jin^1,* , Xiu-Wu Bian^1,*

¹Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
²Department of Oncology, Shandong Second Provincial General Hospital, Jinan, Shandong, China
³Department of Breast Surgery, Fudan University Shanghai Cancer Center; Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
⁴National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
⁵College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
⁶Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
⁷Department of Breast Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence: Guoxiang Jin(gxjinking@hotmail.com)Xiu-Wu Bian(bianxiuwu@263.net)

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.

https://doi.org/10.1038/s41422-022-00766-z

FULL TEXT | PDF

Browse 600