Mukai Hiroki, Miki Nagisa, Yamada Hikari, Goto Haruka, Kawakami Taiko, Suzuki Akari, Yamamoto Kazuhiko, Nakanishi Yusuke, Takahashi Kyoko
College of Bioresource Sciences Graduate School of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa, 252-0880, Japan.
Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Biochem Biophys Res Commun. 2022 Nov 5;628:116-122. doi: 10.1016/j.bbrc.2022.08.062. Epub 2022 Aug 26.
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 neutrophils in 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.
凋亡性细胞死亡是机体发育和组织稳态中的关键步骤。凋亡细胞会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微环境逃避抗肿瘤免疫反应。在此，我们利用小鼠移植模型发现，源自4T1乳腺癌细胞系的肿瘤中有大量肿瘤细胞发生内源性凋亡，且中性粒细胞显著聚集。有趣的是，这些凋亡的4T1肿瘤细胞以泛连接蛋白1（Panx1）通道依赖性方式直接诱导中性粒细胞胞外陷阱（NETs）形成，敲低4T1细胞中的Panx1会导致肿瘤大小减小。凋亡的4T1细胞通过Panx1释放的亚精胺在体外诱导骨髓来源的中性粒细胞形成NETs。此外，抑制亚精胺合成可抑制小鼠移植模型中的肿瘤生长。总体而言，我们的数据表明，内源性凋亡细胞通过Panx1介导的分泌组为肿瘤提供了一种新的免疫逃逸机制，这可能为癌症提供新的治疗靶点。
