Cancer cell CCR2 orchestrates suppression of the adaptive immune response.
Adaptive Immunity
/ immunology
Animals
Apoptosis
B7-H1 Antigen
/ metabolism
Dendritic Cells
/ immunology
Female
Histocompatibility Antigens Class I
/ metabolism
Immune Tolerance
/ immunology
Interferons
/ metabolism
Mammary Neoplasms, Experimental
/ immunology
Mice
Mice, Inbred C57BL
Receptors, CCR2
/ immunology
T-Lymphocytes, Cytotoxic
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
05 10 2020
05 10 2020
Historique:
received:
13
08
2018
revised:
27
12
2019
accepted:
26
05
2020
entrez:
16
7
2020
pubmed:
16
7
2020
medline:
11
3
2021
Statut:
ppublish
Résumé
C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and approximately twofold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as up-regulation of MHC class I and down-regulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2-/- cancer cells did not induce immune suppression in Batf3-/- mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.
Identifiants
pubmed: 32667673
pii: 151949
doi: 10.1084/jem.20181551
pmc: PMC7537399
pii:
doi:
Substances chimiques
B7-H1 Antigen
0
Ccr2 protein, mouse
0
Cd274 protein, mouse
0
Histocompatibility Antigens Class I
0
Receptors, CCR2
0
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Informations de copyright
© 2020 Fein et al.
Déclaration de conflit d'intérêts
Disclosures: M. Egeblad reported "other" from Agios Pharmaceutical, personal fees from MPM Gilead, and personal fees from CytomX outside the submitted work. No other disclosures were reported.
Références
J Leukoc Biol. 2002 Jun;71(6):907-20
pubmed: 12050175
Cancer Cell. 2012 Jul 10;22(1):91-105
pubmed: 22789541
J Immunol. 2015 Aug 15;195(4):1341-9
pubmed: 26254266
Science. 2008 Nov 14;322(5904):1097-100
pubmed: 19008445
Am J Pathol. 2003 Nov;163(5):2113-26
pubmed: 14578209
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Oncoimmunology. 2013 Jul 1;2(7):e25474
pubmed: 24073384
Tumour Biol. 2015 Feb;36(2):973-81
pubmed: 25318604
Cancer Lett. 2008 Aug 28;267(2):271-85
pubmed: 18439751
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cancer Cell. 2017 May 8;31(5):711-723.e4
pubmed: 28486109
Cancer Immunol Res. 2015 Apr;3(4):399-411
pubmed: 25678581
Cancer Cell. 2012 Apr 17;21(4):488-503
pubmed: 22516258
Immunity. 2012 Jun 29;36(6):1031-46
pubmed: 22749353
Nat Immunol. 2002 Nov;3(11):991-8
pubmed: 12407406
Am J Pathol. 2001 Jun;158(6):1997-2003
pubmed: 11395377
J Biol Chem. 2012 Oct 19;287(43):36593-608
pubmed: 22927430
BMC Bioinformatics. 2009 Feb 03;10:48
pubmed: 19192299
Biol Open. 2019 Jun 28;8(7):
pubmed: 31208996
Lancet Oncol. 2016 May;17(5):651-62
pubmed: 27055731
Oncotarget. 2016 May 10;7(19):28697-710
pubmed: 26885690
Proc Natl Acad Sci U S A. 2020 Jan 14;117(2):1129-1138
pubmed: 31879345
Cancer Cell. 2016 Aug 8;30(2):324-336
pubmed: 27424807
Genome Biol. 2014;15(12):550
pubmed: 25516281
Blood. 2014 Nov 13;124(20):3081-91
pubmed: 25100743
Gynecol Oncol. 2001 Oct;83(1):170-1
pubmed: 11585436
J Exp Med. 2000 Oct 2;192(7):1027-34
pubmed: 11015443
J Exp Med. 1992 Dec 1;176(6):1693-702
pubmed: 1460426
Cancer Cell. 2012 Jun 12;21(6):822-35
pubmed: 22698406
PLoS One. 2009 Aug 10;4(8):e6562
pubmed: 19668347
Prostate. 2006 Sep 1;66(12):1311-8
pubmed: 16705739
Int Immunopharmacol. 2013 Feb;15(2):357-63
pubmed: 23246255
Nature. 2014 Nov 6;515(7525):130-3
pubmed: 25337873
Ann Oncol. 2016 Mar;27(3):409-16
pubmed: 26681673
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3628-33
pubmed: 10097088
Cancer Immunol Immunother. 2013 Sep;62(9):1453-61
pubmed: 23771160
PLoS One. 2016 Nov 7;11(11):e0165595
pubmed: 27820834
Cancer Cell. 2014 Nov 10;26(5):638-52
pubmed: 25446897
Cancer Cell. 2012 Jun 12;21(6):836-47
pubmed: 22698407
Int J Cancer. 2016 Jan 15;138(2):271-80
pubmed: 25471439
Nature. 2011 Jun 08;475(7355):222-5
pubmed: 21654748
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
JAKSTAT. 2012 Apr 1;1(2):65-72
pubmed: 24058752
J Clin Invest. 1997 Nov 15;100(10):2552-61
pubmed: 9366570
Cancer Cell. 2018 Jan 8;33(1):60-74.e6
pubmed: 29316433
J Interferon Cytokine Res. 2009 Jun;29(6):313-26
pubmed: 19441883
Nat Commun. 2017 Mar 09;8:14638
pubmed: 28276425
Annu Rev Immunol. 2004;22:329-60
pubmed: 15032581
EMBO Mol Med. 2013 Sep;5(9):1383-401
pubmed: 23982944
Mol Cell Biol. 1992 Mar;12(3):954-61
pubmed: 1312220
Cancer Cell. 2014 Nov 10;26(5):623-37
pubmed: 25446896
Cancer Res. 2016 Mar 15;76(6):1416-28
pubmed: 26719528
Nat Commun. 2018 Mar 28;9(1):1250
pubmed: 29593283
BMC Cancer. 2017 Apr 18;17(1):280
pubmed: 28420351
Nature. 2001 Mar 1;410(6824):50-6
pubmed: 11242036
Tumour Biol. 2004 Jan-Apr;25(1-2):14-7
pubmed: 15192307
Cancer Cell. 2012 Mar 20;21(3):402-17
pubmed: 22439936