Research Papers:

Apolipoprotein A-I mimetic peptide 4F suppresses tumor-associated macrophages and pancreatic cancer progression

Meiyu Peng, Qi Zhang, Yingnan Cheng, Shuyu Fu, Huipeng Yang, Xiangdong Guo, Jieyou Zhang, Lina Wang, Lijuan Zhang, Zhenyi Xue, Yan Li, Yurong Da, Zhi Yao, Liang Qiao and Rongxin Zhang _

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Oncotarget. 2017; 8:99693-99706. https://doi.org/10.18632/oncotarget.21157

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Meiyu Peng1,2,*, Qi Zhang3,2,*, Yingnan Cheng2,*, Shuyu Fu2,4, Huipeng Yang2, Xiangdong Guo2, Jieyou Zhang2, Lina Wang1, Lijuan Zhang2, Zhenyi Xue2, Yan Li2, Yurong Da2, Zhi Yao2, Liang Qiao5 and Rongxin Zhang2,6

1Department of Immunology, School of Clinical Medicine, Weifang Medical University, Weifang, China

2Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Molecular and Cellular Immunology, Tianjin Medical University, Tianjin, China

3Institute of Integrative Medicines for Acute Abdominal Diseases, Nankai Hospital, Tianjin, China

4Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China

5Storr Liver Unit, Westmead Institute for Medical Research, the University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia

6Laboratory of Immunology and Inflammation, School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China

*These authors contributed equally to this work

Correspondence to:

Rongxin Zhang, email: [email protected]

Liang Qiao, email: [email protected]

Meiyu Peng, email: [email protected]

Yurong Da, email: [email protected]

Keywords: pancreatic cancer, L-4F, inflammation, tumor-associated macrophages, STAT3

Received: June 09, 2017     Accepted: September 08, 2017     Published: September 22, 2017


Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.

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