Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.

Bloomberg~Kimmel Institute for Cancer Immunotherapy Sidney Kimmel Comprehensive Cancer Research Center Department of Oncology and

Department of Medicine Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Neuroscience Johns Hopkins Drug Discovery Baltimore Maryland USA

Institute of Organic Chemistry and Biochemistry Prague Czech Republic

UPMC Enterprises Pittsburgh Pennsylvania USA

000      

00000naa a2200000 a 4500

001      

bmc21012425

003      

CZ-PrNML

005      

20210507104722.0

007      

ta

008      

210420s2020 xxu f 000 0|eng||

009      

AR

024    7_

$a 10.1172/JCI131859 $2 doi

035    __

$a (PubMed)32324593

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxu

100    1_

$a Oh, Min-Hee $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and $u Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

245    10

$a Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells / $c MH. Oh, IH. Sun, L. Zhao, RD. Leone, IM. Sun, W. Xu, SL. Collins, AJ. Tam, RL. Blosser, CH. Patel, JM. Englert, ML. Arwood, J. Wen, Y. Chan-Li, L. Tenora, P. Majer, R. Rais, BS. Slusher, MR. Horton, JD. Powell

520    9_

$a Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.

650    _2

$a zvířata $7 D000818

650    _2

$a ženské pohlaví $7 D005260

650    _2

$a glutamin $x imunologie $7 D005973

650    12

$a buněčná imunita $7 D007111

650    _2

$a imunoterapie $7 D007167

650    _2

$a makrofágy $x imunologie $x patologie $7 D008264

650    _2

$a mužské pohlaví $7 D008297

650    _2

$a myši $7 D051379

650    _2

$a myši inbrední BALB C $7 D008807

650    _2

$a myši knockoutované $7 D018345

650    _2

$a myeloidní supresorové buňky $x imunologie $x patologie $7 D000072737

650    _2

$a experimentální nádory $x imunologie $x patologie $x terapie $7 D009374

650    _2

$a nádorové mikroprostředí $x imunologie $7 D059016

655    _2

$a časopisecké články $7 D016428

655    _2

$a Research Support, N.I.H., Extramural $7 D052061

655    _2

$a práce podpořená grantem $7 D013485

700    1_

$a Sun, Im-Hong $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Zhao, Liang $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Leone, Robert D $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Sun, Im-Meng $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Xu, Wei $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Collins, Samuel L $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and $u Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

700    1_

$a Tam, Ada J $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Blosser, Richard L $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Patel, Chirag H $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Englert, Judson M $u UPMC Enterprises, Pittsburgh, Pennsylvania, USA

700    1_

$a Arwood, Matthew L $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Wen, Jiayu $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

700    1_

$a Chan-Li, Yee $u Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

700    1_

$a Tenora, Lukáš $u Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic

700    1_

$a Majer, Pavel $u Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic

700    1_

$a Rais, Rana $u Department of Neuroscience, Johns Hopkins Drug Discovery, Baltimore, Maryland, USA

700    1_

$a Slusher, Barbara S $u Department of Neuroscience, Johns Hopkins Drug Discovery, Baltimore, Maryland, USA

700    1_

$a Horton, Maureen R $u Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

700    1_

$a Powell, Jonathan D $u Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, and

773    0_

$w MED00002590 $t The Journal of clinical investigation $x 1558-8238 $g Roč. 130, č. 7 (2020), s. 3865-3884

856    41

$u https://pubmed.ncbi.nlm.nih.gov/32324593 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20210420 $b ABA008

991    __

$a 20210507104720 $b ABA008

999    __

$a ok $b bmc $g 1650738 $s 1132804

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2020 $b 130 $c 7 $d 3865-3884 $e 20200701 $i 1558-8238 $m The Journal of clinical investigation $n J Clin Invest $x MED00002590

GRA    __

$a P30 CA006973 $p NCI NIH HHS $2 United States

GRA    __

$a R01 NS103927 $p NINDS NIH HHS $2 United States

GRA    __

$a R01 HL141490 $p NHLBI NIH HHS $2 United States

GRA    __

$a R01 CA226765 $p NCI NIH HHS $2 United States

GRA    __

$a R01 CA229451 $p NCI NIH HHS $2 United States

GRA    __

$a R01 AI077610 $p NIAID NIH HHS $2 United States

GRA    __

$a P41 EB028239 $p NIBIB NIH HHS $2 United States

LZP    __

$a Pubmed-20210420