LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma

PLoS Pathogens

Jia He¹  Shu-Biao Ye¹  Yi-Xin Zeng¹  Xiao-Shi Zhang¹  Ting-Ting Cai¹  Jiang Li²  Qiu-Yan Chen²  Hai-Qiang Mai³  Chuan-Xia Zhang³  Yi-Na Liu⁴  Pierre Busson⁵  Jun Cui⁵ 

[1] Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China;Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China;Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China;Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-sen University, Guangzhou, China

关键词: Glycolysis;    Immunoprecipitation;    Inflammasomes;    Enzyme-linked immunoassays;    Cell differentiation;    Glucose metabolism;    Glucose;    Nasopharyngeal carcinoma;   

DOI  :  10.1371/journal.ppat.1006503

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

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