Phosphorylation of SMAD3 in immune cells predicts survival of patients with early stage non-small cell lung cancer.
B7-H1 Antigen
/ metabolism
Carcinoma, Non-Small-Cell Lung
/ metabolism
Case-Control Studies
Forkhead Transcription Factors
/ metabolism
Humans
Lung Neoplasms
/ metabolism
Machine Learning
Neoplasm Staging
Phosphorylation
Retrospective Studies
Signal Transduction
Smad3 Protein
/ metabolism
Survival Analysis
Tissue Array Analysis
Transforming Growth Factor beta
/ metabolism
lung neoplasms
tumor microenvironment
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
accepted:
30
11
2020
entrez:
16
2
2021
pubmed:
17
2
2021
medline:
16
12
2021
Statut:
ppublish
Résumé
The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment. Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data. TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer. TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
Sections du résumé
BACKGROUND
The interplay of immune and cancer cells takes place in the tumor microenvironment where multiple signals are exchanged. The transforming growth factor beta (TGFB) pathway is known to be dysregulated in lung cancer and can impede an effective immune response. However, the exact mechanisms are yet to be determined. Especially which cells respond and where does this signaling take place with respect to the local microenvironment.
METHODS
Human non-small cell lung cancer samples were retrospectively analyzed by multiplexed immunohistochemistry for SMAD3 phosphorylation and programmed death ligand 1 expression in different immune cells with respect to their localization within the tumor tissue. Spatial relationships were studied to examine possible cell-cell interactions and analyzed in conjunction with clinical data.
RESULTS
TGFB pathway activation in CD3, CD8, Foxp3 and CD68 cells, as indicated by SMAD3 phosphorylation, negatively impacts overall and partially disease-free survival of patients with lung cancerindependent of histological subtype. A high frequency of Foxp3 regulatory T cells positive for SMAD3 phosphorylation in close vicinity of CD8 T cells within the tumor discriminate a rapidly progressing group of patients with lung cancer.
CONCLUSIONS
TGFB pathway activation of local immune cells within the tumor microenvironment impacts survival of early stage lung cancer. This might benefit patients not eligible for targeted therapies or immune checkpoint therapy as a therapeutic option to re-activate the local immune response.
Identifiants
pubmed: 33589523
pii: jitc-2020-001469
doi: 10.1136/jitc-2020-001469
pmc: PMC7887360
pii:
doi:
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
FOXP3 protein, human
0
Forkhead Transcription Factors
0
SMAD3 protein, human
0
Smad3 Protein
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Trends Cancer. 2019 Oct;5(10):593-603
pubmed: 31706507
J Thorac Oncol. 2018 Apr;13(4):521-532
pubmed: 29269008
Cancer Biol Ther. 2018 Feb 1;19(2):105-112
pubmed: 29219668
Nat Med. 2013 Nov;19(11):1423-37
pubmed: 24202395
Cancer Cell. 2012 Mar 20;21(3):309-22
pubmed: 22439926
Cell. 2008 Jul 25;134(2):215-30
pubmed: 18662538
Lung Cancer. 2018 Mar;117:73-79
pubmed: 29409671
Science. 2015 Apr 3;348(6230):74-80
pubmed: 25838376
Immunity. 2013 Jul 25;39(1):1-10
pubmed: 23890059
Annu Rev Immunol. 2004;22:329-60
pubmed: 15032581
Nat Commun. 2018 Nov 8;9(1):4692
pubmed: 30410077
Front Immunol. 2019 Apr 12;10:774
pubmed: 31031765
Cell. 2017 Feb 9;168(4):707-723
pubmed: 28187290
Nature. 2018 Feb 22;554(7693):544-548
pubmed: 29443960
Pharmacol Ther. 2018 Apr;184:112-130
pubmed: 29129643
Nature. 2003 Oct 9;425(6958):577-84
pubmed: 14534577
Sci Signal. 2017 Aug 29;10(494):
pubmed: 28851824
N Engl J Med. 2017 Aug 31;377(9):849-861
pubmed: 28854088
Methods Enzymol. 2020;635:1-20
pubmed: 32122539
Cancer Cell. 2005 Nov;8(5):369-80
pubmed: 16286245
Front Oncol. 2020 Jan 21;9:1550
pubmed: 32039023
Cancer Discov. 2016 Dec;6(12):1366-1381
pubmed: 27683557
Cancer Res. 2016 Jul 1;76(13):3785-801
pubmed: 27197161
J Immunol. 2018 Jan 1;200(1):347-354
pubmed: 29141863
Nat Rev Clin Oncol. 2017 Dec;14(12):717-734
pubmed: 28741618
Cell Syst. 2018 Jan 24;6(1):75-89.e11
pubmed: 29248373
Cell. 2018 Oct 4;175(2):313-326
pubmed: 30290139
Pharmacol Ther. 2015 Mar;147:22-31
pubmed: 25444759
Sci Rep. 2018 Feb 13;8(1):2918
pubmed: 29440769
Nature. 2018 Feb 22;554(7693):538-543
pubmed: 29443964
J Thorac Oncol. 2011 Jul;6(7):1162-8
pubmed: 21597388
J Immunol. 2018 Jan 15;200(2):385-391
pubmed: 29311379
JCI Insight. 2017 Jul 20;2(14):
pubmed: 28724788
Oncoimmunology. 2018 Feb 14;7(5):e1426519
pubmed: 29721396
Immunity. 2019 Apr 16;50(4):924-940
pubmed: 30995507
Cold Spring Harb Perspect Biol. 2017 Jun 1;9(6):
pubmed: 28108486
Nature. 2017 Jan 18;541(7637):321-330
pubmed: 28102259
Oncoimmunology. 2017 Jul 13;6(10):e1349589
pubmed: 29123964
Nat Med. 2001 Oct;7(10):1118-22
pubmed: 11590434
J Immunother Cancer. 2019 Aug 13;7(1):216
pubmed: 31409394
Cell Rep. 2017 Apr 4;19(1):203-217
pubmed: 28380359
Cancer Immunol Immunother. 2016 May;65(5):587-99
pubmed: 27000869
Nature. 2015 Jul 9;523(7559):231-5
pubmed: 25970248