Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours.
B7-H1 Antigen
/ drug effects
Cell Line, Tumor
Colorectal Neoplasms
/ pathology
Humans
Interferon-gamma
/ pharmacology
Janus Kinases
/ drug effects
Liver Neoplasms
/ secondary
Molecular Targeted Therapy
Neoplasms
/ genetics
Organoids
Programmed Cell Death 1 Ligand 2 Protein
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-met
/ antagonists & inhibitors
Receptors, Interferon
STAT1 Transcription Factor
/ drug effects
Signal Transduction
Tumor Escape
/ drug effects
Interferon gamma Receptor
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
10
08
2018
accepted:
03
10
2018
revised:
01
10
2018
pubmed:
7
2
2019
medline:
18
12
2019
entrez:
7
2
2019
Statut:
ppublish
Résumé
Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours. PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy. PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-γ treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/ STAT1, signal transducers downstream of the Interferon-γ receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-γ induced PD-L1 expression. These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-γ. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.
Sections du résumé
BACKGROUND
Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immune-evasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-γ modulation of PD-L1/PD-L2 in MET-amplified tumours.
METHODS
PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-γ were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-γ stimulation, and after anti-MET therapy.
RESULTS
PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-γ treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/ STAT1, signal transducers downstream of the Interferon-γ receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-γ induced PD-L1 expression.
CONCLUSIONS
These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-γ. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.
Identifiants
pubmed: 30723303
doi: 10.1038/s41416-018-0315-3
pii: 10.1038/s41416-018-0315-3
pmc: PMC6461865
doi:
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
PDCD1LG2 protein, human
0
Programmed Cell Death 1 Ligand 2 Protein
0
Protein Kinase Inhibitors
0
Receptors, Interferon
0
STAT1 Transcription Factor
0
Interferon-gamma
82115-62-6
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Janus Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
527-536Références
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20852-7
pubmed: 19088198
Lancet. 2016 Apr 9;387(10027):1540-1550
pubmed: 26712084
J Cell Sci. 1998 Jan;111 ( Pt 2):237-47
pubmed: 9405310
Sci Transl Med. 2012 Mar 28;4(127):127ra37
pubmed: 22461641
Annu Rev Pathol. 2016 May 23;11:199-220
pubmed: 26907527
J Clin Invest. 2015 Sep;125(9):3384-91
pubmed: 26325035
Nat Immunol. 2001 Mar;2(3):261-8
pubmed: 11224527
Nat Genet. 1997 May;16(1):68-73
pubmed: 9140397
Clin Cancer Res. 2011 May 15;17(10):3146-56
pubmed: 21447729
N Engl J Med. 2016 Nov 10;375(19):1856-1867
pubmed: 27718784
N Engl J Med. 2015 Nov 5;373(19):1803-13
pubmed: 26406148
Lung Cancer. 2017 Oct;112:200-215
pubmed: 29191596
J Biol Chem. 2001 Dec 21;276(51):47771-4
pubmed: 11694501
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2316-21
pubmed: 16461907
Cancer Discov. 2011 Nov;1(6):508-23
pubmed: 22586653
J Biol Chem. 2008 Dec 5;283(49):34374-83
pubmed: 18819921
Sci Transl Med. 2015 Mar 18;7(279):279ra41
pubmed: 25787767
J Clin Oncol. 2012 Jan 20;30(3):e30-3
pubmed: 22162573
Biochem Biophys Res Commun. 2010 Apr 16;394(4):1042-6
pubmed: 20331976
Clin Cancer Res. 2012 Feb 1;18(3):737-47
pubmed: 22179665
J Clin Oncol. 2011 Dec 20;29(36):4803-10
pubmed: 22042947
J Exp Med. 2000 Oct 2;192(7):1027-34
pubmed: 11015443
J Exp Med. 2014 May 5;211(5):943-59
pubmed: 24752301
N Engl J Med. 2016 Nov 10;375(19):1823-1833
pubmed: 27718847
Invest Ophthalmol Vis Sci. 2008 Jul;49(7):2927-35
pubmed: 18579758
Lancet Oncol. 2017 Nov;18(11):1483-1492
pubmed: 28967485
J Thorac Oncol. 2011 May;6(5):942-6
pubmed: 21623265
Acta Histochem. 2006;108(1):19-24
pubmed: 16530813
Am J Respir Cell Mol Biol. 2005 Sep;33(3):280-9
pubmed: 15961727
Nature. 2015 Jun 18;522(7556):349-53
pubmed: 25985180
Nat Rev Mol Cell Biol. 2010 Dec;11(12):834-48
pubmed: 21102609
Nat Rev Immunol. 2008 Jun;8(6):467-77
pubmed: 18500231
Cell Rep. 2014 Jun 26;7(6):1940-55
pubmed: 24931611
Nature. 2014 Nov 27;515(7528):563-7
pubmed: 25428504
Cancer Discov. 2016 Sep;6(9):963-71
pubmed: 27325282
Mol Endocrinol. 2001 Oct;15(10):1768-80
pubmed: 11579209
J Clin Oncol. 2018 Mar 10;36(8):773-779
pubmed: 29355075
Immunity. 2017 Oct 17;47(4):789-802.e9
pubmed: 29045907
Cancer Discov. 2015 Aug;5(8):802-5
pubmed: 26243862
Cancer Res. 2014 Mar 15;74(6):1857-69
pubmed: 24448239
Lung Cancer. 2017 Jan;103:27-37
pubmed: 28024693
J Cell Biochem. 1987 Oct;35(2):113-28
pubmed: 2448318
Hum Mutat. 2011 Jan;32(1):44-50
pubmed: 20949619
Mol Oncol. 2015 Nov;9(9):1760-72
pubmed: 26119717
Nat Med. 2002 Aug;8(8):793-800
pubmed: 12091876
N Engl J Med. 2017 Oct 5;377(14):1345-1356
pubmed: 28889792
Curr Opin Genet Dev. 2014 Feb;24:68-73
pubmed: 24657539
Curr Oncol Rep. 2016 Jul;18(7):42
pubmed: 27215436
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5
pubmed: 17360651
Clin Cancer Res. 2005 Apr 15;11(8):2947-53
pubmed: 15837746
Cancer Res. 2007 Mar 1;67(5):2081-8
pubmed: 17332337
J Exp Med. 2003 Jun 16;197(12):1721-30
pubmed: 12810690
Cancer Genet Cytogenet. 1992 Dec;64(2):170-3
pubmed: 1486568
Mol Oncol. 2016 Jun;10(6):938-48
pubmed: 27103110
Nat Med. 1999 Dec;5(12):1365-9
pubmed: 10581077
Nat Rev Cancer. 2012 Mar 22;12(4):252-64
pubmed: 22437870
Nat Med. 2007 Jan;13(1):84-8
pubmed: 17159987
Cell Rep. 2017 May 9;19(6):1189-1201
pubmed: 28494868
Science. 2007 May 18;316(5827):1039-43
pubmed: 17463250
Cancer Res. 2006 Apr 1;66(7):3381-5
pubmed: 16585157
J Clin Oncol. 2010 Jul 1;28(19):3167-75
pubmed: 20516446
Cancer Discov. 2013 Jun;3(6):658-73
pubmed: 23729478