Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.
NF-kB
PD-L1
exosomes
glycolysis
immunosuppression
lactate
metastasis
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
05 10 2021
05 10 2021
Historique:
received:
02
06
2020
revised:
01
02
2021
accepted:
07
09
2021
pubmed:
25
9
2021
medline:
8
4
2022
entrez:
24
9
2021
Statut:
ppublish
Résumé
One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.
Identifiants
pubmed: 34559989
pii: S1550-4131(21)00421-6
doi: 10.1016/j.cmet.2021.09.002
pmc: PMC8506837
mid: NIHMS1743372
pii:
doi:
Substances chimiques
R-SNARE Proteins
0
YKT6 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2040-2058.e10Subventions
Organisme : NCI NIH HHS
ID : P01 CA163223
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM135004
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI128818
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213990
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Clin Cancer Res. 2016 Aug 1;22(15):3725-33
pubmed: 27252414
Eur J Pharmacol. 2016 Aug 15;785:24-35
pubmed: 27085899
Mol Cancer. 2019 Aug 13;18(1):124
pubmed: 31409361
Cancer Res. 2019 Feb 15;79(4):795-806
pubmed: 30610087
Int J Clin Oncol. 2017 Dec;22(6):1026-1033
pubmed: 28748356
Cell Metab. 2018 Dec 4;28(6):848-865.e6
pubmed: 30174307
Sci Rep. 2019 Sep 16;9(1):13362
pubmed: 31527660
Cell. 2019 Apr 4;177(2):414-427.e13
pubmed: 30951669
Mol Ther. 2018 Oct 3;26(10):2466-2475
pubmed: 30120059
Blood. 2007 May 1;109(9):3812-9
pubmed: 17255361
Trends Cancer. 2017 Sep;3(9):659-672
pubmed: 28867169
Nature. 2019 Jul;571(7766):570-575
pubmed: 31243362
Cancer Res. 2016 Jan 15;76(2):227-38
pubmed: 26637667
Sci Transl Med. 2019 Feb 13;11(479):
pubmed: 30760579
Oncoimmunology. 2018 Jan 16;7(4):e1412909
pubmed: 29632728
Cancer Res. 2019 Sep 15;79(18):4715-4728
pubmed: 31337655
Sci Immunol. 2017 Jul 28;2(13):
pubmed: 28754746
Blood. 2012 Aug 16;120(7):1422-31
pubmed: 22786879
Oncoimmunology. 2016 Jun 21;5(8):e1191731
pubmed: 27622062
J Clin Invest. 2018 Feb 1;128(2):805-815
pubmed: 29337305
PLoS One. 2015 Dec 23;10(12):e0145342
pubmed: 26699615
Nature. 2014 Sep 25;513(7519):559-63
pubmed: 25043024
J Vis Exp. 2010 Jan 28;(35):
pubmed: 20110936
Clin Cancer Res. 2018 Feb 15;24(4):896-905
pubmed: 29233903
Oncotarget. 2016 Aug 30;7(35):56279-56294
pubmed: 27462921
J Biol Chem. 2013 Dec 20;288(51):36691-702
pubmed: 24225954
Int J Mol Sci. 2019 Jul 05;20(13):
pubmed: 31284422
Mol Med. 2018 May 4;24(1):19
pubmed: 30134807
Nature. 2018 Jan 24;553(7689):446-454
pubmed: 29364287
Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22
pubmed: 18228490
Nature. 2016 Mar 24;531(7595):513-7
pubmed: 26982733
Nature. 2018 Aug;560(7718):382-386
pubmed: 30089911
J Clin Invest. 2018 Feb 1;128(2):580-588
pubmed: 29337303
Nature. 2015 Nov 19;527(7578):329-35
pubmed: 26524530
Cancer Cell. 2016 Nov 14;30(5):668-681
pubmed: 27846389
Chest. 2013 May;143(5 Suppl):e211S-e250S
pubmed: 23649440
Cancer Res. 2019 Jun 1;79(11):2909-2922
pubmed: 30737234
Cancer Cell. 2016 Aug 8;30(2):243-256
pubmed: 27505671
J Lipid Res. 2012 Sep;53(9):2002-13
pubmed: 22766885
Nat Commun. 2018 Jan 2;9(1):21
pubmed: 29295986
Am J Physiol Gastrointest Liver Physiol. 2018 Jan 1;314(1):G22-G31
pubmed: 29025731
Nat Med. 2018 May;24(5):541-550
pubmed: 29686425
Cancer Res. 2011 Apr 1;71(7):2550-60
pubmed: 21300765
Nat Rev Mol Cell Biol. 2018 Apr;19(4):213-228
pubmed: 29339798
N Engl J Med. 2015 Oct 22;373(17):1627-39
pubmed: 26412456
Cell Mol Life Sci. 2018 Jan;75(2):193-208
pubmed: 28733901
J Clin Invest. 2016 Apr 1;126(4):1208-15
pubmed: 27035812
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):
pubmed: 33723042
Oncoimmunology. 2018 Feb 1;7(5):e1423170
pubmed: 29721376
Cancer Res. 2016 Dec 1;76(23):6816-6827
pubmed: 27760789
Mol Cancer. 2019 Mar 1;18(1):32
pubmed: 30823926
Proteomics Clin Appl. 2015 Apr;9(3-4):358-67
pubmed: 25684126
Oncol Lett. 2018 May;15(5):6799-6805
pubmed: 29725415
Am J Pathol. 2010 Oct;177(4):1606-10
pubmed: 20802178
Mol Cancer. 2018 Oct 6;17(1):146
pubmed: 30292233
Nat Med. 2012 Jun;18(6):883-91
pubmed: 22635005
Cytokine. 2018 May;105:63-72
pubmed: 29459345
J Clin Invest. 2012 Mar;122(3):787-95
pubmed: 22378047
Radiographics. 2001 Mar-Apr;21(2):403-17
pubmed: 11259704
Oncotarget. 2016 Aug 9;7(32):51515-51524
pubmed: 27285987
Clin Cancer Res. 2017 Aug 15;23(16):4843-4854
pubmed: 28400428
Sci Adv. 2018 Mar 07;4(3):eaar2766
pubmed: 29532035
Shock. 2006 Aug;26(2):174-9
pubmed: 16878026
Stem Cell Res Ther. 2018 Jul 4;9(1):180
pubmed: 29973270
Nature. 2019 Oct;574(7779):575-580
pubmed: 31645732