Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction

被引：338

作者：

Zhao, Ende ^{[1
,2
]}

Maj, Tomasz ^{[1
]}

Kryczek, Ilona ^{[1
]}

Li, Wei ^{[1
,2
]}

Wu, Ke ^{[1
,2
]}

Zhao, Lili ^{[3
]}

Wei, Shuang ^{[1
]}

Crespo, Joel ^{[1
]}

Wan, Shanshan ^{[1
]}

Vatan, Linda ^{[1
]}

Szeliga, Wojciech ^{[1
]}

Shao, Irene ^{[1
]}

Wang, Yin ^{[1
]}

Liu, Yan ^{[1
]}

Varambally, Sooryanarayana ^{[4
,5
]}

Chinnaiyan, Arul M. ^{[5
]}

Welling, Theodore H. ^{[1
]}

Marquez, Victor ^{[6
]}

Kotarski, Jan ^{[7
]}

Wang, Hongbo ^{[8
]}

Wang, Zehua ^{[8
]}

Zhang, Yi ^{[9
]}

Liu, Rebecca ^{[10
]}

Wang, Guobin

Zou, Weiping ^{[1
,11
,12
]}

机构：

[1] Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA

[2] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Surg, Wuhan 430074, Peoples R China

[3] Univ Michigan, Sch Med, Dept Biostat, Ann Arbor, MI USA

[4] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

[5] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA

[6] NCI, Ctr Canc Res, Biol Chem Lab, Frederick, MD 21701 USA

[7] Med Univ Lublin, Dept Gynecol Oncol & Gynecol 1, Lublin, Poland

[8] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Obstet & Gynecol, Wuhan 430074, Peoples R China

[9] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA

[10] Univ Michigan, Sch Med, Dept Obstet & Gynecol, Ann Arbor, MI USA

[11] Univ Michigan, Grad Programs Immunol & Canc Biol, Ann Arbor, MI 48109 USA

[12] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

来源：

NATURE IMMUNOLOGY | 2016年 / 17卷 / 01期

基金：

美国国家卫生研究院;

关键词：

HISTONE METHYLTRANSFERASE EZH2; GROUP PROTEIN EZH2; TH17; CELLS; SURVIVAL; EXPRESSION; STEMNESS; DIFFERENTIATION; METHYLATION; REPRESSION; INHIBITOR;

D O I：

10.1038/ni.3313

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：95 / +

页数：11

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