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// Jinhoi Song 1, 2, * , Jaemin Lee 1, * , Jinsil Kim 1, * , Seongyea Jo 1 , Yeon Jeong Kim 3 , Ji Eun Baek 3 , Eun-Soo Kwon 1 , Kwang-Pyo Lee 1 , Siyoung Yang 1 , Ki-Sun Kwon 1 , Dong-Uk Kim 1 , Tae Heung Kang 4 , Yun-Yong Park 5 , Suhwan Chang 6 , Hee Jun Cho 7 , Song Cheol Kim 8 , Sang Seok Koh 3 , Seokho Kim 1 1 Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea 3 Department of Biological Sciences, Dong-A University, Busan, Republic of Korea 4 Department of Immunology, School of Medicine, Konkuk University, Seoul, Republic of Korea 5 Department of Biomedical Sciences and Physiology, University of Ulsan College of Medicine, Seoul, Republic of Korea 6 Departments of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 7 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 8 Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Song-Cheol Kim, email: drksc@amc.seoul.kr Sang Seok Koh, email: sskoh@dau.ac.kr Seokho Kim, email: kims@kribb.re.kr Keywords: MDSC, PAUF, pancreatic cancer, tumor microenvironment Received: November 30, 2015 Accepted: May 28, 2016 Published: June 17, 2016 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.

The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death-a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner.