- 作者: Feng-Wei Chen, Yung-Ling Wu, Chao-Chun Cheng, Yu-Wei Hsiao, Jhih-Ying Chi, Liang-Yi Hung, Chih-Peng Chang, Ming-Derg Lai & Ju-Ming Wang
- 作者服務機構: 1.Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1 University Rd., Tainan, 70101, Taiwan 2.Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, No. 1 University Rd., Tainan, 70101, Taiwan 3.Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 4.Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 5.Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 6.Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan 7.International Research Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- 中文摘要:
- 英文摘要:
Background
The tumor microenvironment is characterized by inflammation-like and immunosuppression situations. Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon cancer, the interactions between CAFs and immune cells remains largely uncharacterized. Pentraxin 3 (PTX3) is responsive to proinflammatory cytokines and modulates immunity and tissue remodeling, but its involvement in tumor progression appears to be context-dependent and is unclear.
Methods
Open-access databases were utilized to examine the association of PTX3 expression and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen-induced Ptx3 knockout mice and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced promotion of M2 macrophage polarization.
Results
Clinically, higher PTX3 expression was positively correlated with fibroblasts and inflammatory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of PTX3 significantly reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the cytotoxic CD8+ T-cell population were observed following PTX3 inactivation in allografted colon tumors. We further revealed that activation of cyclic AMP-responsive element-binding protein 1 (CREB1) mediated the PTX3-induced promotion of M2 macrophage polarization.
Conclusions
PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2-like macrophage polarization, and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer. - 中文關鍵字:
- 英文關鍵字: PTX3, Cancer-associated fbroblasts, M2-like macrophages, Colon cancer, Immunosuppression