IL27 Signaling Serves as an Immunologic Checkpoint for Innate Cytotoxic Cells to Promote Hepatocellular Carcinoma.
Antineoplastic Agents
/ therapeutic use
Carcinoma, Hepatocellular
/ immunology
Humans
Immunity, Innate
/ genetics
Interleukin-27
/ immunology
Interleukins
/ immunology
Liver Neoplasms
/ immunology
Prognosis
Receptors, Interleukin
/ immunology
Signal Transduction
T-Lymphocytes, Cytotoxic
/ immunology
Tumor Microenvironment
/ immunology
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
05 08 2022
05 08 2022
Historique:
received:
07
11
2020
revised:
01
04
2022
accepted:
03
06
2022
pubmed:
21
6
2022
medline:
9
8
2022
entrez:
20
6
2022
Statut:
ppublish
Résumé
Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825.
Identifiants
pubmed: 35723626
pii: 699403
doi: 10.1158/2159-8290.CD-20-1628
pmc: PMC9357073
mid: NIHMS1816190
doi:
Substances chimiques
Antineoplastic Agents
0
IL27RA protein, human
0
Interleukin-27
0
Interleukins
0
MYDGF protein, human
0
Receptors, Interleukin
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1960-1983Subventions
Organisme : NCI NIH HHS
ID : R01 CA273925
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010877
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227629
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010876
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI110985
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218133
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA202396
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011870
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL149946
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010313
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133669
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
Références
Sci Rep. 2019 Mar 21;9(1):4984
pubmed: 30899058
J Autoimmun. 2009 Feb;32(1):43-51
pubmed: 19101114
Annu Rev Immunol. 2015;33:417-43
pubmed: 25861977
Clin Cancer Res. 2016 Aug 1;22(15):3876-83
pubmed: 26979394
Nat Immunol. 2021 Oct;22(10):1256-1267
pubmed: 34462601
Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H420-9
pubmed: 23729211
BMC Genomics. 2018 Jun 19;19(1):477
pubmed: 29914354
Nat Commun. 2021 Jun 9;12(1):3500
pubmed: 34108491
World J Hepatol. 2015 Aug 18;7(17):2110-8
pubmed: 26301053
Semin Immunol. 2014 Apr;26(2):138-44
pubmed: 24629893
Immunity. 2002 Jun;16(6):779-90
pubmed: 12121660
Expert Rev Gastroenterol Hepatol. 2015 Jun;9(6):765-79
pubmed: 25827821
Science. 2011 Mar 25;331(6024):1565-70
pubmed: 21436444
Science. 2018 May 25;360(6391):
pubmed: 29798856
Immunotherapy. 2014;6(12):1265-78
pubmed: 25524383
Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):11808-11813
pubmed: 30381460
Immunity. 2012 Dec 14;37(6):960-9
pubmed: 23244718
Nature. 2018 Jun;558(7710):454-459
pubmed: 29899446
Cancers (Basel). 2019 Jul 30;11(8):
pubmed: 31366113
J Hepatol. 2019 Mar;70(3):531-544
pubmed: 30414863
Am J Clin Oncol. 2018 Sep;41(9):874-881
pubmed: 28537989
Nature. 2017 Nov 16;551(7680):340-345
pubmed: 29144460
J Biomed Biotechnol. 2010;2010:605483
pubmed: 20454646
Nat Immunol. 2018 Dec;19(12):1330-1340
pubmed: 30420624
Hepatology. 2013 Apr;57(4):1654-62
pubmed: 23111952
Hepatology. 2020 Jan;71(1):363-374
pubmed: 31230380
Nat Rev Immunol. 2019 May;19(5):282-290
pubmed: 30808985
J Immunol. 2010 Aug 15;185(4):2482-92
pubmed: 20631310
Science. 2018 Dec 21;362(6421):1416-1422
pubmed: 30573629
World J Gastroenterol. 2015 Oct 21;21(39):11077-87
pubmed: 26494963
J Immunol. 2004 Dec 15;173(12):7170-82
pubmed: 15585838
Immunol Rev. 2008 Dec;226:234-47
pubmed: 19161428
Cell. 2018 Aug 23;174(5):1054-1066
pubmed: 30142344
Cancer Cell. 2008 Aug 12;14(2):156-65
pubmed: 18691550
Nat Commun. 2019 Nov 6;10(1):5046
pubmed: 31695038
Nat Immunol. 2013 Oct;14(10):996-1006
pubmed: 24048121
J Immunol. 2010 Dec 15;185(12):7480-6
pubmed: 21076062
Cell Metab. 2019 Jan 8;29(1):18-26
pubmed: 30449681
PLoS Biol. 2018 Apr 27;16(4):e2004867
pubmed: 29702643
Sci Rep. 2016 May 23;6:26157
pubmed: 27210614
J Immunol. 2007 Sep 1;179(5):3268-75
pubmed: 17709543
J Leukoc Biol. 2019 Jun;105(6):1331-1340
pubmed: 30779432
Gastroenterology. 2012 May;142(6):1264-1273.e1
pubmed: 22537432
J Immunol. 2009 May 1;182(9):5748-56
pubmed: 19380822
Cell. 2019 Oct 31;179(4):829-845.e20
pubmed: 31675496
Nat Methods. 2015 May;12(5):453-7
pubmed: 25822800
Front Immunol. 2019 Sep 20;10:2235
pubmed: 31616419
Cancer Res. 2010 Apr 15;70(8):3034-41
pubmed: 20395200
Immunity. 2018 Nov 20;49(5):971-986.e5
pubmed: 30413361
J Hepatocell Carcinoma. 2016 Oct 05;3:41-53
pubmed: 27785449
Cancer Epidemiol Biomarkers Prev. 2021 Feb;30(2):388-395
pubmed: 33203693
J Hepatol. 2012 Aug;57(2):430-41
pubmed: 22504331
Nat Immunol. 2018 Mar;19(3):222-232
pubmed: 29379119
Am J Pathol. 2000 Dec;157(6):1963-74
pubmed: 11106569
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Blood. 2003 Jun 15;101(12):4887-93
pubmed: 12586624
J Immunother. 2010 Nov-Dec;33(9):945-55
pubmed: 20948442
Nat Immunol. 2006 May;7(5):517-23
pubmed: 16565719
Cancer Cell. 2014 Oct 13;26(4):549-64
pubmed: 25314080
PLoS One. 2013;8(3):e57469
pubmed: 23554861
Cancer Res. 2014 Apr 1;74(7):1969-82
pubmed: 24525743
Methods Mol Biol. 2010;612:325-34
pubmed: 20033651
Nat Protoc. 2008;3(7):1167-70
pubmed: 18600221
Cancer Cell. 2019 Oct 14;36(4):418-430.e6
pubmed: 31588021
Nat Immunol. 2006 Sep;7(9):937-45
pubmed: 16906166
Cancer Res. 2010 Dec 15;70(24):10202-12
pubmed: 21159642
Immunol Rev. 2008 Aug;224:70-84
pubmed: 18759921
Stem Cells. 2013 Sep;31(9):1829-39
pubmed: 23733329
Int J Mol Sci. 2019 Feb 15;20(4):
pubmed: 30781344
Int J Mol Sci. 2017 Aug 02;18(8):
pubmed: 28767057
Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604
pubmed: 31439937
Front Immunol. 2019 May 07;10:909
pubmed: 31134055
Gastroenterology. 2019 May;156(6):1877-1889.e4
pubmed: 30710528
Int J Cancer. 2019 Apr 15;144(8):1941-1953
pubmed: 30350310
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Clin Immunol. 2008 Dec;129(3):428-37
pubmed: 18824414
Am J Pathol. 2001 Nov;159(5):1763-76
pubmed: 11696437
Int J Clin Exp Pathol. 2008 Jan 01;1(2):117-23
pubmed: 18784808
Immunity. 2016 May 17;44(5):1005-19
pubmed: 27192566
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Immunol. 2015 Mar;16(3):306-17
pubmed: 25621825
Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G568-76
pubmed: 21193526
Cell. 2010 Jan 22;140(2):197-208
pubmed: 20141834
Circ Res. 2012 Oct 26;111(10):1274-85
pubmed: 22927332
Hepatology. 2016 Mar;63(3):1000-12
pubmed: 26637970
J Immunol. 2011 Apr 1;186(7):3911-7
pubmed: 21335486
Annu Rev Immunol. 2013;31:413-41
pubmed: 23298206
Immunity. 2021 Jun 8;54(6):1320-1337.e4
pubmed: 33945787
Semin Immunol. 2021 Feb;52:101424
pubmed: 33272899
Int Immunopharmacol. 2019 Aug;73:10-16
pubmed: 31078921
Immunity. 2003 Nov;19(5):645-55
pubmed: 14614852
Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3324-9
pubmed: 21300876
Nat Commun. 2019 Jun 3;10(1):2387
pubmed: 31160572
Nat Commun. 2020 Mar 5;11(1):1201
pubmed: 32139671
Transl Oncol. 2020 Jan;13(1):57-69
pubmed: 31785429
Gut. 2017 Feb;66(2):342-351
pubmed: 26669617
J Gastrointest Oncol. 2017 Apr;8(2):229-242
pubmed: 28480063
Front Immunol. 2013 Dec 12;4:450
pubmed: 24376448
Cancer Cell. 2014 Sep 8;26(3):331-343
pubmed: 25132496
Immunity. 2018 Jun 19;48(6):1172-1182.e6
pubmed: 29858012
Int Immunol. 2008 Feb;20(2):223-34
pubmed: 18156621
Mol Cell. 2019 Aug 8;75(3):644-660.e5
pubmed: 31398325
Mol Oncol. 2013 Apr;7(2):206-23
pubmed: 23428636
Nat Immunol. 2017 Nov;18(11):1197-1206
pubmed: 28920951
Sci Rep. 2017 May 23;7(1):2255
pubmed: 28536468
J Immunol. 2006 Feb 1;176(3):1517-24
pubmed: 16424180
Science. 2007 Jul 6;317(5834):121-4
pubmed: 17615358
Immunity. 2001 Oct;15(4):569-78
pubmed: 11672539
J Immunol. 2009 Apr 1;182(7):4328-38
pubmed: 19299733
NAR Genom Bioinform. 2020 Sep;2(3):lqaa078
pubmed: 33015620
J Autoimmun. 2016 Jan;66:40-50
pubmed: 26330348
Annu Rev Immunol. 2013;31:227-58
pubmed: 23516982