Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance

被引：277

作者：

Liu, Yi ^{[1
]}

Liang, Guanghao ^{[2
,3
]}

Xu, Hongjiao ^{[4
,5
]}

Dong, Wenxin ^{[1
]}

Dong, Ze ^{[4
,5
]}

Qiu, Zhiwei ^{[1
]}

Zhang, Zihao ^{[1
]}

Li, Fangle ^{[2
,3
]}

Huang, Yue ^{[4
,5
,6
]}

Li, Yilin ^{[1
]}

Wu, Jun ^{[7
]}

Yin, Shenyi ^{[8
]}

Zhang, Yawei ^{[2
,3
]}

Guo, Peijin ^{[1
]}

Liu, Jun ^{[9
,10
]}

Xi, Jianzhong Jeff ^{[8
]}

Jiang, Peng ^{[7
]}

Han, Dali ^{[2
,3
,11
,12
]}

Yang, Cai-Guang ^{[4
,5
,6
]}

Xu, Meng Michelle ^{[1
]}

机构：

[1] Tsinghua Univ, THU PKU Ctr Life Sci, Sch Med, Inst Immunol,Dept Basic Med Sci,Beijing Key Lab I, Beijing 100084, Peoples R China

[2] Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China

[3] Univ Chinese Acad Sci, Coll Future Technol, Sino Danish Coll, Beijing 100049, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[5] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[6] Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China

[7] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China

[8] Peking Univ, Coll Engn, Dept Biomed Engn, State Key Lab Nat & Biomimet Drugs,Inst Mol Med, Beijing 100871, Peoples R China

[9] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[10] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[11] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China

[12] China Natl Ctr Bioinformat, Beijing 100101, Peoples R China

来源：

CELL METABOLISM | 2021年 / 33卷 / 06期

基金：

中国国家自然科学基金; 北京市自然科学基金; 国家重点研发计划;

关键词：

DENDRITIC CELLS; SELF-RENEWAL; RNA; RESISTANCE; EXPRESSION; DEMETHYLASE; TARGET; MECHANISMS; ULTRAFAST; CHROMATIN;

D O I：

10.1016/j.cmet.2021.04.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The ever-increasing understanding of the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes, Here, we have identified the m(6)A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m(6)A demethylation in tumor cells elevates the transcription factors c-Jun, JunB, and C/EBP beta, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8(+) T cells, thereby inhibiting tumor-growth. Furthermore, we developed a small-molecule compound, Dac51 , that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.

引用

页码：1221 / +

页数：24

共 82 条

[1] The ENCODE Blacklist: Identification of Problematic Regions of the Genome [J].

Amemiya, Haley M. ;

Kundaje, Anshul ;

Boyle, Alan P. .

SCIENTIFIC REPORTS, 2019, 9 (1)

[2] LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells [J].

Brand, Almut ;

Singer, Katrin ;

Koehl, Gudrun E. ;

Kolitzus, Marlene ;

Schoenhammer, Gabriele ;

Thiel, Annette ;

Matos, Carina ;

Bruss, Christina ;

Klobuch, Sebastian ;

Peter, Katrin ;

Kastenberger, Michael ;

Bogdan, Christian ;

Schleicher, Ulrike ;

Mackensen, Andreas ;

Ullrich, Evelyn ;

Fichtner-Feigl, Stefan ;

Kesselring, Rebecca ;

Mack, Matthias ;

Ritter, Uwe ;

Schmid, Maximilian ;

Blank, Christian ;

Dettmer, Katja ;

Oefner, Peter J. ;

Hoffmann, Petra ;

Walenta, Stefan ;

Geissler, Edward K. ;

Pouyssegur, Jacques ;

Villunger, Andreas ;

Steven, Andre ;

Seliger, Barbara ;

Schreml, Stephan ;

Haferkamp, Sebastian ;

Kohl, Elisabeth ;

Karrer, Sigrid ;

Berneburg, Mark ;

Herr, Wolfgang ;

Mueller-Klieser, Wolfgang ;

Renner, Kathrin ;

Kreutz, Marina .

Cell Metabolism, 2016, 24 (05) :657-671

[3] Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen-Presenting Cells Critical for T Cell Immunity [J].

Broz, Miranda L. ;

Binnewies, Mikhail ;

Boldajipour, Bijan ;

Nelson, Amanda E. ;

Pollack, Joshua L. ;

Erle, David J. ;

Barczak, Andrea ;

Rosenblum, Michael D. ;

Daud, Adil ;

Barber, Diane L. ;

Amigorena, Sebastian ;

van't Veer, Laura J. ;

Sperling, Anne I. ;

Wolf, Denise M. ;

Krummel, Matthew F. .

CANCER CELL, 2014, 26 (05) :638-652

[4]

Buenrostro JD, 2013, NAT METHODS, V10, P1213, DOI [10.1038/NMETH.2688, 10.1038/nmeth.2688]

[5] An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer [J].

Burr, Marian L. ;

Sparbier, Christina E. ;

Chan, Kah Lok ;

Chan, Yih-Chih ;

Kersbergen, Ariena ;

Lam, Enid Y. N. ;

Azidis-Yates, Elizabeth ;

Vassiliadis, Dane ;

Bell, Charles C. ;

Gilan, Omer ;

Jackson, Susan ;

Tan, Lavinia ;

Wong, Stephen Q. ;

Hollizeck, Sebastian ;

Michalak, Ewa M. ;

Siddle, Hannah, V ;

McCabe, Michael T. ;

Prinjha, Rab K. ;

Guerra, Glen R. ;

Solomon, Benjamin J. ;

Sandhu, Shahneen ;

Dawson, Sarah-Jane ;

Beavis, Paul A. ;

Tothill, Richard W. ;

Cullinane, Carleen ;

Lehner, Paul J. ;

Sutherland, Kate D. ;

Dawson, Mark A. .

CANCER CELL, 2019, 36 (04) :385-+

[6] Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy [J].

Cascone, Tina ;

McKenzie, Jodi A. ;

Mbofung, Rina M. ;

Punt, Simone ;

Wang, Zhe ;

Xu, Chunyu ;

Williams, Leila J. ;

Wang, Zhiqiang ;

Bristow, Christopher A. ;

Carugo, Alessandro ;

Peoples, Michael D. ;

Li, Lerong ;

Karpinets, Tatiana ;

Huang, Lu ;

Malu, Shruti ;

Creasy, Caitlin ;

Leahey, Sara E. ;

Chen, Jiong ;

Chen, Yuan ;

Pelicano, Helen ;

Bernatchez, Chantale ;

Gopal, Y. N. Vashisht ;

Heffernan, Timothy P. ;

Hu, Jianhua ;

Wang, Jing ;

Amaria, Rodabe N. ;

Garraway, Levi A. ;

Huang, Peng ;

Yang, Peiying ;

Wistuba, Ignacio I. ;

Woodman, Scott E. ;

Roszik, Jason ;

Davis, R. Eric ;

Davies, Michael A. ;

Heymach, John V. ;

Hwu, Patrick ;

Peng, Weiyi .

CELL METABOLISM, 2018, 27 (05) :977-+

[7] MYC regulates the antitumor immune response through CD47 and PD-L1 [J].

Casey, Stephanie C. ;

Tong, Ling ;

Li, Yulin ;

Do, Rachel ;

Walz, Susanne ;

Fitzgerald, Kelly N. ;

Gouw, Arvin M. ;

Baylot, Virginie ;

Guetgemann, Ines ;

Eilers, Martin ;

Felsher, Dean W. .

SCIENCE, 2016, 352 (6282) :227-231

[8] Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression [J].

Chang, Chih-Hao ;

Qiu, Jing ;

O'Sullivan, David ;

Buck, Michael D. ;

Noguchi, Takuro ;

Curtis, Jonathan D. ;

Chen, Qiongyu ;

Gindin, Mariel ;

Gubin, Matthew M. ;

van der Windt, Gerritje J. W. ;

Tonc, Elena ;

Schreiber, Robert D. ;

Pearce, Edward J. ;

Pearce, Erika L. .

CELL, 2015, 162 (06) :1229-1241

[9] Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study [J].

Cohen, Ezra E. W. ;

Soulieres, Denis ;

Le Tourneau, Christophe ;

Dinis, Jose ;

Licitra, Lisa ;

Ahn, Myung-Ju ;

Soria, Ainara ;

Machiels, Jean-Pascal ;

Mach, Nicolas ;

Mehra, Ranee ;

Burtness, Barbara ;

Zhang, Pingye ;

Cheng, Jonathan ;

Swaby, Ramona F. ;

Harrington, Kevin J. .

LANCET, 2019, 393 (10167) :156-167

[10] TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data [J].

Colaprico, Antonio ;

Silva, Tiago C. ;

Olsen, Catharina ;

Garofano, Luciano ;

Cava, Claudia ;

Garolini, Davide ;

Sabedot, Thais S. ;

Malta, Tathiane M. ;

Pagnotta, Stefano M. ;

Castiglioni, Isabella ;

Ceccarelli, Michele ;

Bontempi, Gianluca ;

Noushmehr, Houtan .

NUCLEIC ACIDS RESEARCH, 2016, 44 (08) :e71

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