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

  • Cell Res. 2023 Jan 10. doi: 10.1038/s41422-022-00766-z.
Xiao-Qing Xie  1 ,  Yi Yang  1 ,  Qiang Wang  1  2 ,  Hao-Fei Liu  1 ,  Xuan-Yu Fang  1 ,  Cheng-Long Li  1 ,  Yi-Zhou Jiang  3 ,  Shuai Wang  1 ,  Hong-Yu Zhao  4  5 ,  Jing-Ya Miao  1 ,  Shuai-Shuai Ding  1 ,  Xin-Dong Liu  1 ,  Xiao-Hong Yao  1 ,  Wen-Tao Yang  6 ,  Jun Jiang  7 ,  Zhi-Ming Shao  3 ,  Guoxiang Jin  8 ,  Xiu-Wu Bian  9
Affiliations
  • 1. Institute 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.
  • 2. Department of Oncology, Shandong Second Provincial General Hospital, Jinan, Shandong, China.
  • 3. Department of Breast Surgery, Fudan University Shanghai Cancer Center; Key Laboratory of Breast Cancer in Shanghai, Shanghai, China.
  • 4. National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 6. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 7. Department of Breast Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 8. Institute 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. [email protected].
  • 9. Institute 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. [email protected].
PMID: 36627348 DOI: 10.1038/s41422-022-00766-z
Abstract

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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