Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

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 (T reg ), 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; T reg 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 T reg depletion appear to be of benefit, but still require validation before being recommended in the clinical setting.

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression

“…In addition to the metabolic roles, CAFs are also at the center of the immunosuppressive PDAC microenvironment (23)(24)(25)(26). CAFs exert immunosuppressive effects through direct modulation of immune cell function via cytokine secretion ( 27 ), exclusion of antitumor immune cells from the tumor ( 28 ), and/or recruitment of immunosuppressive immune cells to the tumor ( 29 ).…”

SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

“…Yet these therapeutic approaches are often unsuccessful, particularly in pancreatic cancer patients [ 38 ]. This failure depends on several factors, including the complexity of the genetic alterations and tumor heterogeneity, the plasticity of tumor cells that enable them to activate alternative signalling pathways when one of them is antagonized, and the multiplicity of inflammatory molecules and growth factors from the stromal compartment, which might support EGFR-independent tumor cell growth and invasion [ 4 , 20 , 23 , 39 – 41 ]. The aim of the present study was to improve our understanding of the way in which EGF governs the pancreatic cancer cell response to relevant stromal derived molecules, TGFβ1 and S100A8/A9, while also investigating whether SMAD4 participates in this complex scenario.…”

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

“…This is an interesting observation that may explain the suboptimal cytotoxic response of effector T cells, but in-depth investigation is required to further validate the role of MUC4 in mediating tumor cell-cytotoxic T-lymphocyte (CTL) interactions. In addition to infiltrating immunosuppressive and inflammatory immune cells [45], pancreatic tumors are characterized by low abundance of effector CD8 + T cells which in part, can be attributed to MUC4-mediated apoptosis. Therefore, MUC4 in PDAC might play a crucial role in establishing an immunosuppressive TME [45,46].…”

“…In addition to infiltrating immunosuppressive and inflammatory immune cells [45], pancreatic tumors are characterized by low abundance of effector CD8 + T cells which in part, can be attributed to MUC4-mediated apoptosis. Therefore, MUC4 in PDAC might play a crucial role in establishing an immunosuppressive TME [45,46]. …”