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

Jinhoi Song,Sang Seok Koh,Eun-Soo Kwon,Yeon Jeong Kim,Hee Jun Cho,Suhwan Chang,Kwang-Pyo Lee,Seongyea Jo,Dong-Uk Kim,Ki-Sun Kwon,Siyoung Yang,Yun-Yong Park,Seokho Kim,Tae Heung Kang,Jinsil Kim,Song Cheol Kim,Ji Eun Baek,Jaemin Lee

doi:10.18632/oncotarget.10123

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.

Highlights

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of < 8% [1]
pancreatic adenocarcinoma up-regulated factor (PAUF) contributes to the increasing proportion of myeloid-derived suppressor cells (MDSCs) population in pancreatic cancers Previously, it has been shown that PAUF plays an important role in tumor progression and metastasis in pancreatic cancer [24, 25, 27]
The proportion of the MDSCs population was significantly increased in spleen and pancreatic tumor tissues from PANC-1/PAUF-Luc cell-injected mice compared to control mice injected with PANC-1/Mock-Luc cells (Figure 1A)

Summary

Introduction

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of < 8% [1]. Despite long-term and ongoing efforts, there has been little success in improving the survival rate; this may be attributed to late diagnoses, its high metastatic ability, and its resistance to therapeutic agents [2]. The pancreatic tumor stroma is comprised of a plethora of cellular and acellular components, including fibroblasts, pancreatic stellate cells, immune cells, endothelial cells, extracellular matrix, and soluble proteins such as cytokines and growth factors [3]. This heterogeneous tumor microenvironment (TME) changes in composition over the course of cancer development, influencing tumor growth, invasion, and sensitivity to therapeutics [3, 4]. They facilitate tumor progression by blocking antitumor immunity through the inhibition of T-cell proliferation, activation, and function, and their critical role in driving immune suppression in the TME makes them an important target for cancer immunotherapy [15, 17, 18]

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Results

Conclusion