Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3. Issue 1 (18th September 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal for immunotherapy of cancer. Volume 7:Issue 1(2019)
• Publication Date: 2019-09-18
• Subjects: Myeloid-derived suppressor cells (MDSC) -- Pancreatic ductal adenocarcinoma (PDAC) -- Innate immunity -- Tumor-associated immunosuppression -- Tumor progression; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-019-0734-6
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.