Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment
Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment
复制标题
凋亡肿瘤细胞的 Pannexin1 通道依赖性分泌组塑造免疫逃逸微环境
DOI：
10.1016/j.bbrc.2022.08.062
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发表时间：
2022
影响因子：
3.1
通讯作者：
Takahashi Kyoko
中科院分区：
文献类型：
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作者：
Mukai Hiroki;Miki Nagisa;Yamada Hikari;Goto Haruka;Kawakami Taiko;Suzuki Akari;Yamamoto Kazuhiko;Nakanishi Yusuke;Takahashi Kyoko
细胞凋亡是生物体发育和组织稳态的关键步骤。凋亡细胞影响正常组织中的免疫细胞活性。目前尚不清楚类似的细胞死亡机制是否会导致肿瘤环境逃避抗肿瘤免疫反应。在这里，使用小鼠移植模型，我们发现了大量的肿瘤细胞进行内在凋亡的肿瘤来源于4T1乳腺癌细胞系，其中嗜中性粒细胞显着积累。有趣的是，这些凋亡的4T1肿瘤细胞以泛连接蛋白1（Panx 1）通道依赖性方式直接诱导中性粒细胞胞外陷阱（NET），并且在4T1细胞中敲低Panx 1导致肿瘤大小减小。凋亡4T1细胞通过Panx1释放的亚精胺诱导骨髓源性嗜中性粒细胞产生NETs此外，在小鼠移植模型中，抑制亚精胺合成抑制肿瘤生长。总的来说，我们的数据表明了一种新的免疫逃逸机制，通过Panx 1介导的内源性凋亡细胞分泌组，这可能为癌症提供一个新的治疗靶点。
Apoptotic cell death is a critical step in organism development and tissue homeostasis. Apoptotic cells affect immune cell activities in normal tissues. It is not clear whether similar cell death machinery causes tumor environments to evade anti-tumor immune responses. Here, using a mouse transplant model, we found a large number of tumor cells undergoing intrinsic apoptosis in tumors derived from the 4T1 breast cancer cell line, where neutrophils significantly accumulated. Interestingly, these apoptotic 4T1 tumor cells directly induced neutrophil extracellular traps (NETs) in a pannexin 1 (Panx1) channel-dependent manner, and knockdown of Panx1 in 4T1 cells led to a reduction in tumor size. Spermidine released through Panx1 from apoptotic 4T1 cells induced NETs in bone marrow-derived neutrophilsin vitro. In addition, inhibition of spermidine synthesis suppressed tumor growth in the mouse transplant model. Collectively, our data suggested a new immune-escape mechanism for tumors by Panx1-mediated secretome from intrinsic apoptotic cells, which may provide a new therapeutic target for cancer.