Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer

Abstract

Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.

Elevated expression of pancreatic adenocarcinoma upregulated factor (PAUF) is associated with poor prognosis and chemoresistance in epithelial ovarian cancer

“…Song et al . reported that PAUF enhances accumulation of tumor-infiltrating Myeloid-derived suppressor cells and its immune suppressive function via TLR4-mediated signaling pathway in PAUF-overexpressing tumor cell-injected mice 39 . With further studies, specific activation or repression of PAUF/TLRs can be harnessed to offer novel immunotherapies or adjuvants to traditional chemotherapy for some ovarian cancer patients.…”

The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma

“…Other soluble factors that have been associated with the recruitment of MDSCs by pancreatic cancer cells include granulocyte/macrophage colony-stimulating factor (GM-CSF) [ 174 ] and pancreatic adenocarcinoma upregulated factor (PAUF), a soluble protein previously implicated in pancreatic cancer metastasis [ 175 ]. PAUF has been suggested to attract MDSCs to tumor sites in an SDF-1-dependent manner by upregulating the expression of CXCR4 on MDSCs.…”

The role of toll-like receptor 4 in tumor microenvironment

“…The ability of BMDMs, stimulated by NTC-Ms, to induce apoptosis of activated T cells was suppressed by an inhibitor of TRIF pathway [ 65 ], suggesting that TLR4 ligands in NTC-Ms aroused the apoptosis-inducing capability of Gr-1+CD11b+F4/80+ BMDMs, which was further confirmed by the use of sTLR4 expression vector in palpable tumor [ 64 ]. PAUF, a soluble protein involved in pancreatic tumorigenesis and metastasis, interacted with TLR4 on the surface of MDSCs and enhanced their immunosuppressive effects on activated T cells in tumor microenvironment [ 66 ]. Furthermore, wilde et al have found that repetitive injections of LPS induced a cluster of MDSC-like cells, which mediate suppression of T cell response on vitro [ 67 ].…”