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

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 ac...

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Detalles Bibliográficos
Autores principales: Trovato, Rosalinda, Fiore, Alessandra, Sartori, Sara, Canè, Stefania, Giugno, Rosalba, Cascione, Luciano, Paiella, Salvatore, Salvia, Roberto, De Sanctis, Francesco, Poffe, Ornella, Anselmi, Cristina, Hofer, Francesca, Sartoris, Silvia, Piro, Geny, Carbone, Carmine, Corbo, Vincenzo, Lawlor, Rita, Solito, Samantha, Pinton, Laura, Mandruzzato, Susanna, Bassi, Claudio, Scarpa, Aldo, Bronte, Vincenzo, Ugel, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751612/
https://www.ncbi.nlm.nih.gov/pubmed/31533831
http://dx.doi.org/10.1186/s40425-019-0734-6
Descripción
Sumario: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(+) cells. CONCLUSION: MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.