Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer
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Jinhoi Song1,2,*, Jaemin Lee1,*, Jinsil Kim1,*, Seongyea Jo1, Yeon Jeong Kim3, Ji Eun Baek3, Eun-Soo Kwon1, Kwang-Pyo Lee1, Siyoung Yang1, Ki-Sun Kwon1, Dong-Uk Kim1, Tae Heung Kang4, Yun-Yong Park5, Suhwan Chang6, Hee Jun Cho7, Song Cheol Kim8, Sang Seok Koh3, Seokho Kim1
1Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
2Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea
3Department of Biological Sciences, Dong-A University, Busan, Republic of Korea
4Department of Immunology, School of Medicine, Konkuk University, Seoul, Republic of Korea
5Department of Biomedical Sciences and Physiology, University of Ulsan College of Medicine, Seoul, Republic of Korea
6Departments of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
7Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
8Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, Republic of Korea
*These authors have contributed equally to this work
Song-Cheol Kim, email: [email protected]
Sang Seok Koh, email: [email protected]
Seokho Kim, email: [email protected]
Keywords: MDSC, PAUF, pancreatic cancer, tumor microenvironment
Received: November 30, 2015 Accepted: May 28, 2016 Published: June 17, 2016
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.
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