Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer.
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.
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea.
Jinhoi
J
Song
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Jaemin
J
Lee
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Jinsil
J
Kim
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Seongyea
S
Jo
Department of Biological Sciences, Dong-A University, Busan, Republic of Korea.
Yeon Jeong
YJ
Kim
Department of Biological Sciences, Dong-A University, Busan, Republic of Korea.
Ji Eun
JE
Baek
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Eun-Soo
ES
Kwon
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Kwang-Pyo
KP
Lee
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Siyoung
S
Yang
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Ki-Sun
KS
Kwon
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Dong-Uk
DU
Kim
Department of Immunology, School of Medicine, Konkuk University, Seoul, Republic of Korea.
Tae Heung
TH
Kang
Department of Biomedical Sciences and Physiology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yun-Yong
YY
Park
Departments of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Suhwan
S
Chang
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Hee Jun
HJ
Cho
Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, Republic of Korea.
Song Cheol
SC
Kim
Department of Biological Sciences, Dong-A University, Busan, Republic of Korea.
Sang Seok
SS
Koh
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Seokho
S
Kim
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D008565:Membrane Proteins; C487135:ZG-16 protein, mouse; C517340:ZG16B protein, human
MDSC; PAUF; pancreatic cancer; tumor microenvironment