Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

被引：847

作者：

Leone, Robert D. ^{[1
]}

Zhao, Liang ^{[1
]}

Englert, Judson M. ^{[1
]}

Sun, Im-Meng ^{[1
]}

Oh, Min-Hee ^{[1
]}

Sun, Im-Hong ^{[1
]}

Arwood, Matthew L. ^{[1
]}

Bettencourt, Ian A. ^{[1
]}

Patel, Chirag H. ^{[1
]}

Wen, Jiayu ^{[1
]}

Tam, Ada ^{[1
]}

Blosser, Richard L. ^{[1
]}

Prchalova, Eva ^{[2
]}

Alt, Jesse ^{[2
]}

Rais, Rana ^{[2
]}

Slusher, Barbara S. ^{[2
]}

Powell, Jonathan D. ^{[1
]}

机构：

[1] Johns Hopkins, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD 21287 USA

[2] Johns Hopkins Sch Med, Johns Hopkins Drug Discovery, Baltimore, MD 21205 USA

来源：

SCIENCE | 2019年 / 366卷 / 6468期

基金：

美国国家卫生研究院;

关键词：

PYRUVATE-CARBOXYLASE; PHASE-II; 6-DIAZO-5-OXO-L-NORLEUCINE DON; T-CELLS; CANCER; MYC; INHIBITION; REGULATOR; DELIVERY; PRODRUG;

D O I：

10.1126/science.aav2588

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.

引用

页码：1013 / +

页数：41

共 57 条

[1] From Krebs to clinic: glutamine metabolism to cancer therapy [J].

Altman, Brian J. ;

Stine, Zachary E. ;

Dang, Chi V. .

NATURE REVIEWS CANCER, 2016, 16 (10) :619-634

[2]

[Anonymous], 1959, J NATL CANCER I, V22, P433

[3]

BAKKER A., 1927, KLIN WOCHENSCHR, V6, P252, DOI 10.1007/BF01710710

[4] Memory CD8+ T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function [J].

Balmer, Maria L. ;

Ma, Eric H. ;

Bantug, Glenn R. ;

Grahlert, Jasmin ;

Pfister, Simona ;

Glatter, Timo ;

Jauch, Annaise ;

Dimeloe, Sarah ;

Slack, Emma ;

Dehio, Philippe ;

Krzyzaniak, Magdalena A. ;

King, Carolyn G. ;

Burgener, Anne-Valerie ;

Fischer, Marco ;

Develioglu, Leyla ;

Belle, Reka ;

Recher, Mike ;

Bonilla, Weldy V. ;

Macpherson, Andrew J. ;

Hapfelmeier, Siegfried ;

Jones, Russell G. ;

Hess, Christoph .

IMMUNITY, 2016, 44 (06) :1312-1324

[5] 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

[6] Pyruvate carboxylase is required for glutamine-independent growth of tumor cells [J].

Cheng, Tzuling ;

Sudderth, Jessica ;

Yang, Chendong ;

Mullen, Andrew R. ;

Jin, Eunsook S. ;

Mates, Jose M. ;

DeBerardinis, Ralph J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (21) :8674-8679

[7] CCCTC-Binding Factor Translates Interleukin 2-and α-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs [J].

Chisolm, Danielle A. ;

Savic, Daniel ;

Moore, Amanda J. ;

Ballesteros-Tato, Andre ;

Leon, Beatriz ;

Crossman, David K. ;

Murre, Cornelis ;

Myers, Richard M. ;

Weinmann, Amy S. .

IMMUNITY, 2017, 47 (02) :251-+

[8] Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer [J].

Davidson, Shawn M. ;

Papagiannakopoulos, Thales ;

Olenchock, Benjamin A. ;

Heyman, Julia E. ;

Keibler, Mark A. ;

Luengo, Alba ;

Bauer, Matthew R. ;

Jha, Abhishek K. ;

O'Brien, James P. ;

Pierce, Kerry A. ;

Gui, Dan Y. ;

Sullivan, Lucas B. ;

Wasylenko, Thomas M. ;

Subbaraj, Lakshmipriya ;

Chin, Christopher R. ;

Stephanopolous, Gregory ;

Mott, Bryan T. ;

Jacks, Tyler ;

Clish, Clary B. ;

Heiden, Matthew G. Vander .

CELL METABOLISM, 2016, 23 (03) :517-528

[9] The MYC mRNA 3′-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels [J].

Dejure, Francesca R. ;

Royla, Nadine ;

Herold, Steffi ;

Kalb, Jacqueline ;

Walz, Susanne ;

Ade, Carsten P. ;

Mastrobuoni, Guido ;

Vanselow, Jens T. ;

Schlosser, Andreas ;

Wolf, Elmar ;

Kempa, Stefan ;

Eilers, Martin .

EMBO JOURNAL, 2017, 36 (13) :1854-1868

[10] Metabolic influences that regulate dendritic cell function in tumors [J].

Dong, Han ;

Bullock, Timothy N. J. .

FRONTIERS IN IMMUNOLOGY, 2014, 5

← 1 2 3 4 5 6 →