线粒体分裂
细胞生物学
CD8型
下调和上调
T细胞
程序性细胞死亡
生物
运动性
癌症研究
细胞毒性T细胞
信号转导
化学
免疫系统
细胞凋亡
线粒体
免疫学
生物化学
体外
基因
作者
Luca Simula,Ylenia Antonucci,Giorgia Scarpelli,Valeria Cancila,Alessandra Colamatteo,Simona Manni,Biagio De Angelis,Concetta Quintarelli,Claudio Procaccini,Giuseppe Matarese,Claudio Tripodo,Silvia Campello
标识
DOI:10.1002/1878-0261.13103
摘要
Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1neg counterparts. Also, PD-1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondrial fragmentation following T-cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1pos CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.
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