Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 7, Issue 1, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1186/s40425-019-0734-6
Keywords
Myeloid-derived suppressor cells (MDSC); Pancreatic ductal adenocarcinoma (PDAC); Innate immunity; Tumor-associated immunosuppression; Tumor progression
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Funding
- VB grants [18603, 12182]
- Italian Association for Cancer Research (AIRC)
- Cancer Research Institute (Clinic and Laboratory Integration Program)
- Euronanomed III
- Cariverona Fondation
- Qatar National Priority Research Program [NPRP11S-1211-170086]
- University of Verona [RF-2016-02361940]
- Italian Association for Cancer Research (AIRC) [21509]
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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.
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