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

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

doi:10.1038/ni.3313

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

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 WangZehua Wang, Yi Zhang, Rebecca Liu, Guobin Wang, Weiping Zou^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

335 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	95-103
Number of pages	9
Journal	Nature Immunology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1038/ni.3313
State	Published - Jan 1 2016

Funding

We thank D. Postiff, M. Vinco, R. Craig and J. Barikdar for tissue procurement core at the University of Michigan; G. Lv, W. Dong and L. Li for assistance; R. Zhang (Wistar Institute) for shEZH2 plasmids; P. King for discussions; and B. Leclair and D. Leclair for support. Supported by the US National Institutes of Health (the Intramural Research Program; and CA123088, CA099985, CA156685, CA171306 and 5P30CA46592), the Chinese Ministry of Science and Technology (973 program, 2015CB554000), the Wuhan Union Hospital Research Fund, the Ovarian Cancer Research Fund, and Marsha Rivkin Center for Ovarian Cancer Research.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ni.3313

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Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., Szeliga, W., Shao, I., Wang, Y., Liu, Y., Varambally, S., Chinnaiyan, A. M., Welling, T. H., Marquez, V., Kotarski, J., ... Zou, W. (2016). Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nature Immunology, 17(1), 95-103. https://doi.org/10.1038/ni.3313

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title = "Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction",

abstract = "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.",

author = "Ende Zhao and Tomasz Maj and Ilona Kryczek and Wei Li and Ke Wu and Lili Zhao and Shuang Wei and Joel Crespo and Shanshan Wan and Linda Vatan and Wojciech Szeliga and Irene Shao and Yin Wang and Yan Liu and Sooryanarayana Varambally and Chinnaiyan, {Arul M.} and Welling, {Theodore H.} and Victor Marquez and Jan Kotarski and Hongbo Wang and Zehua Wang and Yi Zhang and Rebecca Liu and Guobin Wang and Weiping Zou",

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

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doi = "10.1038/ni.3313",

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Zhao, E, Maj, T, Kryczek, I, Li, W, Wu, K, Zhao, L, Wei, S, Crespo, J, Wan, S, Vatan, L, Szeliga, W, Shao, I, Wang, Y, Liu, Y, Varambally, S, Chinnaiyan, AM, Welling, TH, Marquez, V, Kotarski, J, Wang, H, Wang, Z, Zhang, Y, Liu, R, Wang, G & Zou, W 2016, 'Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction', Nature Immunology, vol. 17, no. 1, pp. 95-103. https://doi.org/10.1038/ni.3313

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T1 - Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction

AU - Zhao, Ende

AU - Maj, Tomasz

AU - Kryczek, Ilona

AU - Li, Wei

AU - Wu, Ke

AU - Zhao, Lili

AU - Wei, Shuang

AU - Crespo, Joel

AU - Wan, Shanshan

AU - Vatan, Linda

AU - Szeliga, Wojciech

AU - Shao, Irene

AU - Wang, Yin

AU - Liu, Yan

AU - Varambally, Sooryanarayana

AU - Chinnaiyan, Arul M.

AU - Welling, Theodore H.

AU - Marquez, Victor

AU - Kotarski, Jan

AU - Wang, Hongbo

AU - Wang, Zehua

AU - Zhang, Yi

AU - Liu, Rebecca

AU - Wang, Guobin

AU - Zou, Weiping

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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