Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3.
Aged
Aged, 80 and over
Arginase
/ immunology
Carcinoma, Pancreatic Ductal
/ blood
Cell Separation
Cells, Cultured
Female
Flow Cytometry
Gene Expression Profiling
Humans
Lipopolysaccharide Receptors
/ immunology
Male
Middle Aged
Myeloid-Derived Suppressor Cells
/ immunology
Pancreas
/ immunology
Pancreatic Neoplasms
/ blood
Primary Cell Culture
Prognosis
Prospective Studies
STAT3 Transcription Factor
/ immunology
Signal Transduction
/ immunology
Survival Analysis
Tumor Escape
Tumor Microenvironment
/ immunology
Innate immunity
Myeloid-derived suppressor cells (MDSC)
Pancreatic ductal adenocarcinoma (PDAC)
Tumor progression
Tumor-associated immunosuppression
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:
18 09 2019
18 09 2019
Historique:
received:
12
06
2019
accepted:
05
09
2019
entrez:
20
9
2019
pubmed:
20
9
2019
medline:
4
8
2020
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14 MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.
Sections du résumé
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells.
METHODS
The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity.
RESULTS
Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14
CONCLUSION
MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.
Identifiants
pubmed: 31533831
doi: 10.1186/s40425-019-0734-6
pii: 10.1186/s40425-019-0734-6
pmc: PMC6751612
doi:
Substances chimiques
CD14 protein, human
0
Lipopolysaccharide Receptors
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
ARG1 protein, human
EC 3.5.3.1
Arginase
EC 3.5.3.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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