Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.
Xiao-Qing XieYi YangQiang WangHao-Fei LiuXuan-Yu FangCheng-Long LiYi-Zhou JiangShuai WangHong-Yu ZhaoJing-Ya MiaoShuai-Shuai DingXin-Dong LiuXiao-Hong YaoWen-Tao YangJun JiangZhi-Ming ShaoGuoxiang JinXiu-Wu BianPublished in: Cell research (2023)
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.
Keyphrases
- combination therapy
- cell death
- poor prognosis
- chemotherapy induced
- free survival
- reactive oxygen species
- cancer therapy
- endoplasmic reticulum
- stem cells
- oxidative stress
- binding protein
- drug delivery
- squamous cell carcinoma
- nlrp inflammasome
- single cell
- epidermal growth factor receptor
- bone marrow
- cell therapy
- advanced non small cell lung cancer
- locally advanced
- smoking cessation
- replacement therapy
- rectal cancer