CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.
Aged
Benzylamines
Carcinoma, Pancreatic Ductal
Chemokine CXCL12
Colorectal Neoplasms
/ metabolism
Cyclams
Female
Heterocyclic Compounds
/ antagonists & inhibitors
Humans
Immunity
/ immunology
Immunotherapy
Male
Middle Aged
Pancreas
/ metabolism
Pancreatic Neoplasms
/ metabolism
Receptors, CCR2
/ metabolism
Receptors, CXCR3
/ metabolism
Receptors, CXCR4
/ drug effects
Receptors, CXCR5
/ metabolism
Receptors, CXCR6
/ metabolism
Receptors, Interleukin-8A
/ metabolism
Signal Transduction
/ drug effects
Tumor Microenvironment
/ immunology
Pancreatic Neoplasms
AMD3100
CXCR4
colorectal cancer
immunotherapy
pancreatic cancer
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
17 11 2020
17 11 2020
Historique:
pubmed:
1
11
2020
medline:
26
1
2021
entrez:
31
10
2020
Statut:
ppublish
Résumé
Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
Identifiants
pubmed: 33127761
pii: 2013644117
doi: 10.1073/pnas.2013644117
pmc: PMC7682333
doi:
Substances chimiques
Benzylamines
0
CCR2 protein, human
0
CXCL12 protein, human
0
CXCR3 protein, human
0
CXCR4 protein, human
0
CXCR5 protein, human
0
CXCR6 protein, human
0
Chemokine CXCL12
0
Cyclams
0
Heterocyclic Compounds
0
Receptors, CCR2
0
Receptors, CXCR3
0
Receptors, CXCR4
0
Receptors, CXCR5
0
Receptors, CXCR6
0
Receptors, Interleukin-8A
0
plerixafor
S915P5499N
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
28960-28970Subventions
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L006197/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/S300011/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : Cancer Research UK
ID : C14303/A17197
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C9545/A29580
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00025/12
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C42738/A24868
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: Sanofi provided study drug for the clinical trial and validation of the pharmacokinetics assay, but had no part in study design, data acquisition, data analysis, or manuscript preparation. N.R. and D.G. are co-founders, shareholders, and officers or consultants of Inivata Ltd., a cancer genomics company that commercializes ctDNA analysis. Inivata had no role in the conceptualization, study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Références
Cell Metab. 2016 Nov 8;24(5):672-684
pubmed: 27829137
Nature. 2020 Jan;577(7791):556-560
pubmed: 31942077
Nat Med. 2020 Jun;26(6):878-885
pubmed: 32451495
Cancer Res. 1999 Oct 1;59(19):5002-11
pubmed: 10519415
Curr Opin Immunol. 2017 Apr;45:103-111
pubmed: 28319729
J Clin Oncol. 2016 May 1;34(13):1510-7
pubmed: 26951310
Science. 2010 Nov 5;330(6005):827-30
pubmed: 21051638
Nature. 2020 Jan;577(7791):561-565
pubmed: 31942071
Cancer Res. 2019 Mar 15;79(6):1214-1225
pubmed: 30541742
Nat Rev Cancer. 2017 Apr;17(4):223-238
pubmed: 28233803
Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12139-44
pubmed: 25092322
Science. 2015 Apr 3;348(6230):56-61
pubmed: 25838373
Cell. 2017 Nov 2;171(4):934-949.e16
pubmed: 29033130
Nat Commun. 2019 Sep 13;10(1):4186
pubmed: 31519915
Oncotarget. 2017 Jan 31;8(5):7452-7463
pubmed: 27980218
N Engl J Med. 2012 Jun 28;366(26):2455-65
pubmed: 22658128
Front Immunol. 2012 Sep 11;3:285
pubmed: 22973278
Annu Rev Immunol. 2019 Apr 26;37:457-495
pubmed: 30676822
Cell. 2005 May 6;121(3):335-48
pubmed: 15882617
Nat Rev Clin Oncol. 2018 Oct;15(10):639-650
pubmed: 30050094
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7
pubmed: 24277834
N Engl J Med. 2010 Aug 19;363(8):711-23
pubmed: 20525992
Science. 2018 Mar 23;359(6382):1366-1370
pubmed: 29567708
Nat Med. 2020 May;26(5):693-698
pubmed: 32405063
Nature. 2020 Jan;577(7791):549-555
pubmed: 31942075
PLoS Med. 2016 Dec 20;13(12):e1002198
pubmed: 27997533
Annu Rev Immunol. 2019 Apr 26;37:173-200
pubmed: 30550719
Genome Biol. 2014;15(12):550
pubmed: 25516281
Am J Transplant. 2013 Mar;13(3):645-55
pubmed: 23356949
Proc Natl Acad Sci U S A. 1990 Sep;87(18):7235-9
pubmed: 2402505
Cancer Cell. 2019 Feb 11;35(2):238-255.e6
pubmed: 30753825
N Engl J Med. 2012 Jun 28;366(26):2443-54
pubmed: 22658127
Nat Med. 2015 Aug;21(8):938-945
pubmed: 26193342
Sci Transl Med. 2018 Nov 7;10(466):
pubmed: 30404863
J Biol Chem. 2002 Jul 5;277(27):24515-21
pubmed: 11923301
Clin Cancer Res. 2014 Nov 15;20(22):5697-707
pubmed: 25224278
Ann Oncol. 2017 Aug 1;28(8):1988-1995
pubmed: 28595336
Science. 1999 Feb 5;283(5403):845-8
pubmed: 9933168
Nat Rev Cancer. 2020 Mar;20(3):174-186
pubmed: 31980749
Clin Cancer Res. 2009 Dec 1;15(23):7412-20
pubmed: 19934295
Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13490-13497
pubmed: 31213547
J Exp Med. 2019 Oct 7;216(10):2242-2252
pubmed: 31324739
J Acquir Immune Defic Syndr. 2004 Oct 1;37(2):1253-62
pubmed: 15385732
Am J Respir Crit Care Med. 2014 Apr 1;189(7):832-44
pubmed: 24484236
Nat Rev Immunol. 2011 May;11(5):355-63
pubmed: 21494268
Am J Transplant. 2013 Sep;13(9):2352-63
pubmed: 23915426