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

Trovato, R.; Fiore, A.; Sartori, S.; Cane, S.; Giugno, R.; Cascione, L.; Paiella, S.; Salvia, R.; De Sanctis, F.; Poffe, O.; Anselmi, C.; Hofer, F.; Sartoris, S.; Piro, G.; Carbone, C.; Corbo, V.; Lawlor, R.; Solito, S.; Pinton, L.; Mandruzzato, S.; Bassi, C.; Scarpa, A.; Bronte, V.; Ugel, S.

doi:10.1186/s40425-019-0734-6

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

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Fiore, A.
Murray, Peter / Immunoregulation, Max Planck Institute of Biochemistry, Max Planck Society;

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Trovato, R., Fiore, A., Sartori, S., Cane, S., Giugno, R., Cascione, L., et al. (2019). Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3. Journal for Immunotherapy of Cancer, 7(1): 255. doi:10.1186/s40425-019-0734-6.

Cite as: https://hdl.handle.net/21.11116/0000-000A-AAD6-5

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.