Journal Article

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Bronte, Vincenzo, Ugel, Stefano, Paiella, Salvatore, Giugno, Rosalba, Lawlor, Rita, Piro, Geny, Mandruzzato, Susanna, Trovato, Rosalinda, Sartoris, Silvia, Sartori, Sara, Anselmi, Cristina, Pinton, Laura, Carbone, Carmine, Bassi, Claudio, Fiore, Alessandra, Solito, Samantha, Scarpa, Aldo, Cascione, Luciano, Salvia, Roberto, Hofer, Francesca, Poffe, Ornella, De Sanctis, Francesco, Canè, Stefania, Corbo, Vincenzo

2019

Overview

BackgroundPancreatic 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.MethodsThe 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.ResultsCorrelation 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+ cells.ConclusionMDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.

• Publisher: BMJ Publishing Group Ltd,BioMed Central,BioMed Central Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Age / Aged / Aged, 80 and over / Arginase - immunology / Arginase - metabolism / Biopsy / Cancer / Carcinoma, Pancreatic Ductal - blood / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - mortality / Carcinoma, Pancreatic Ductal - pathology / Cell Separation / Cells, Cultured / Cloning / Diagnosis / Female / Flow Cytometry / Gender / Gene expression / Gene Expression Profiling / Granulocytes / Humans / Immunology / Immunotherapy / Immunotherapy Biomarkers / Innate immunity / Lipopolysaccharide Receptors - immunology / Lipopolysaccharide Receptors - metabolism / Localization / Lymphocytes / Macrophages / Male / Medical prognosis / Medicine / Medicine & Public Health / Middle Aged / Myeloid-derived suppressor cells (MDSC) / Myeloid-Derived Suppressor Cells - immunology / Myeloid-Derived Suppressor Cells - metabolism / Oncology / Pancreas - immunology / Pancreas - pathology / Pancreatic cancer / Pancreatic ductal adenocarcinoma (PDAC) / Pancreatic Neoplasms - blood / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - mortality / Pancreatic Neoplasms - pathology / Primary Cell Culture / Prognosis / Prospective Studies / Reagents / Research Article / Signal Transduction - immunology / Software / STAT3 Transcription Factor - immunology / STAT3 Transcription Factor - metabolism / Statistical analysis / Survival Analysis / T cells / Tumor Escape / Tumor Microenvironment - immunology / Tumor progression / Tumor-associated immunosuppression