第三军医大学卞修武等研究人员合作发现，靶向ATAD3A-PINK1-线粒体自噬轴可克服化疗免疫疗法的抗性。2023年1月10日，《细胞研究》杂志在线发表了这项成果。

研究人员发现免疫检查点抑制剂（ICI）加紫杉醇的治疗反应与PD-L1的亚细胞重新分布有关。在ICI联合nab-紫杉醇的免疫治疗队列中，来自应答者的肿瘤样本显示PD-L1在线粒体的显著分布，而非应答者显示PD-L1在肿瘤细胞膜而非线粒体上的积累增加。这些结果还显示，PD-L1的分布模式受到ATAD3A-PINK1轴的调节。从机制上讲，PINK1将PD-L1招募到线粒体，通过线粒体自噬途径进行降解。重要的是，紫杉醇增加了ATAD3A的表达，通过抑制PINK1依赖性的线粒体，从而破坏了PD-L1的蛋白稳态。在临床上，在使用ICI联合紫杉醇治疗前检测到ATAD3A高表达的肿瘤患者与ATAD3A低表达的肿瘤患者相比，其无进展生存期明显缩短。临床前结果进一步证明，靶向ATAD3A可重置有利的抗肿瘤免疫微环境，并提高ICI加紫杉醇联合治疗的疗效。

总之，这些结果表明，ATAD3A不仅通过阻止PD-L1线粒体分布作为ICI加紫杉醇联合治疗的耐药因素，而且也是提高化疗免疫疗法治疗响应的一个有望靶点。

附：英文原文

Author: 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

Issue&Volume: 2023-01-10

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.

DOI: 10.1038/s41422-022-00766-z

Source: https://www.nature.com/articles/s41422-022-00766-z