Abstract
The high progression rate of Pancreatic Ductal Adenocarcinoma (PDAC) depends on intrinsic genetic and epigenetic cancer cell aberrations and a profound imbalance in immune system cells infiltrating the PDAC stroma. Direct or exosome mediated shedding in the tumor microenviroment of different molecules (e.g. cytokines, chemokines, lectins) causes tumor, pancreatic stellate and inflammatory cells to recruit numerous immunosuppressive cells in the PDAC microenvironment and inhibit immune effector cells. CD8+ T and dendritic immune effector cells (DCs) are reduced, while immunosuppressive T regulatory cells (Treg), Myeloid Derived Suppressor Cells (MDSCs) and M2 Tumor Associated Macrophages (TAMs) accumulate in the PDAC stroma, mainly at the invasive front area. The imbalance in CD4+ T cell subsets, with Th2 and Th17 prevailing over the Th1 effector arm, is associated with a worse PDAC prognosis that depends on the failure of immune system cells to destroy cancer cells, and the accumulation of immune cells in the PDAC stroma can have pro-neoplastic and prometastatic effects. CD4+ T cells are indispensable for PDAC development; Treg and M2 polarized TAMs favor neoangiogenesis and the epithelial to mesenchymal transition of PDAC cells, a pre-requisite for metastases; MDSCs favor metastases by releasing pro-metastatic inflammatory mediators such as S100A8/A9 proteins, and by creating pre-metastatic niches (in metastatic sites). Of the several treatment strategies aiming to abolish the immune cell imbalance in PDAC, and targeting the immune system, DCs manipulation, vaccination with tumor derived antigens and Treg depletion appear to be of benefit, but still require validation before being recommended in the clinical setting.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies, is refractory to treatment, and the fourth leading cause of cancer related death in the developed world, with 46,420 new estimated cases and 39,590 estimated deaths in the US for the year 2014 [1]
The imbalance in CD4+ T cell subsets, with Th2 and Th17 prevailing over the Th1 effector arm, is associated with a worse Pancreatic Ductal Adenocarcinoma (PDAC) prognosis that depends on the failure of immune system cells to destroy cancer cells, and the accumulation of immune cells in the PDAC stroma can have pro-neoplastic and prometastatic effects
In agreement with the hypothesis that an impaired immune response to cancer cells contributes to favoring tumor progression, and in view of the role played by dendritic immune effector cells (DCs) in activating the immune response, it has been demonstrated that high levels of circulating DCs are an independent favorable prognostic factor in patients with resectable and unresectable PDAC [129,130]; similar findings were made on considering patients with tumor infiltrating DCs [131]
Summary
Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies, is refractory to treatment, and the fourth leading cause of cancer related death in the developed world, with 46,420 new estimated cases and 39,590 estimated deaths in the US for the year 2014 [1]. CD8+ T and dendritic immune effector cells (DCs) are reduced, while immunosuppressive T regulatory cells (Treg), Myeloid Derived Suppressor Cells (MDSCs) and M2 Tumor Associated Macrophages (TAMs) accumulate in the PDAC stroma, mainly at the invasive front area.
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