Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction
Authors:
Ende Zhao, Tomasz Maj, Ilona Kryczek, Wei Li, Ke Wu, Lili Zhao, Shuang Wei, Joel Crespo, Shanshan Wan, Linda Vatan, Wojciech Szeliga, Irene Shao, Yin Wang, Yan Liu, Sooryanarayana Varambally, Arul M Chinnaiyan, Theodore H Welling, Victor Marquez, Jan Kotarski, Hongbo Wang, Zehua Wang, Yi Zhang, Rebecca Liu, Guobin Wang, & Weiping Zou
Summary:
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA–mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2+CD8+ T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
Source: Nature Immunology; (11/02/15)
Summary:
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA–mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2+CD8+ T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
Source: Nature Immunology; (11/02/15)