Open AccessLMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma
Author(s) -
Ting Cai,
Shu Biao Ye,
Yi Na Liu,
Jia He,
Qiu Yan Chen,
Hai Qiang,
Chuan xia Zhang,
Jun Cui,
Xiao Shi Zhang,
P. Busson,
Yi Xin Zeng,
Jiang Li
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006503
Subject(s) - tumor microenvironment , nasopharyngeal carcinoma , glut1 , cancer research , inflammasome , myeloid derived suppressor cell , tumor progression , chemistry , glucose transporter , biology , immunology , cancer , inflammation , suppressor , medicine , insulin , genetics , tumor cells , endocrinology , radiation therapy
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.