Cai Ting-Ting, Ye Shu-Biao, Liu Yi-Na, He Jia, Chen Qiu-Yan, Mai Hai-Qiang, Zhang Chuan-Xia, Cui Jun, Zhang Xiao-Shi, Busson Pierre, Zeng Yi-Xin, Li Jiang
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
PLoS Pathog. 2017 Jul 21;13(7):e1006503. doi: 10.1371/journal.ppat.1006503. eCollection 2017 Jul.
Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.
髓系来源的抑制性细胞（MDSCs）在肿瘤微环境中会扩增，包括在爱泼斯坦-巴尔病毒（EBV）相关的鼻咽癌（NPC）微环境中。NPC中MDSC扩增与EBV感染之间的联系尚不清楚。在此，我们表明EBV潜伏膜蛋白1（LMP1）通过促进恶性细胞的线粒体外糖酵解来促进肿瘤微环境中MDSC的扩增，这是一种免疫逃逸情况，最初是由在肿瘤切片中频繁同时检测到大量LMP1、葡萄糖转运蛋白1（GLUT1）和CD33+ MDSCs所提示的。整个过程已在体外重建。LMP1促进包括GLUT1在内的多个糖酵解基因的表达。这种代谢重编程导致Nod样受体家族蛋白3（NLRP3）炎性小体、COX-2和P-p65的表达增加，进而导致IL-1β、IL-6和GM-CSF的产生增加。最后，恶性细胞环境中的这些变化导致源自NPC的MDSC诱导增强。关键步骤之一是LMP1与GLUT1的物理相互作用，通过阻断其K48-泛素化和p62依赖性自噬溶酶体降解来稳定GLUT1蛋白。这项工作表明，LMP1介导的糖酵解通过NLRP3炎性小体、COX-2和P-p65信号通路调节IL-1β、IL-6和GM-CSF的产生，以增强肿瘤相关MDSC的扩增，从而导致NPC中的肿瘤免疫抑制。
