Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon cancer.

IF 9 2区 医学 Q1 CELL BIOLOGY
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
{"title":"Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon cancer.","authors":"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","doi":"10.1186/s12929-023-00991-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>+</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":"31 1","pages":"10"},"PeriodicalIF":9.0000,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10799366/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biomedical Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12929-023-00991-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

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.

五肽 3 失活可抑制结肠癌中 M2 样巨噬细胞的活性和免疫抑制。
背景:肿瘤微环境的特点是炎症样和免疫抑制情况。尽管癌相关成纤维细胞(CAFs)是包括结肠癌在内的各种实体瘤的主要基质细胞类型之一,但CAFs与免疫细胞之间的相互作用在很大程度上仍未得到表征。五胜肽 3(Pentraxin 3,PTX3)对促炎细胞因子有反应,并能调节免疫和组织重塑,但它在肿瘤进展中的参与似乎取决于具体情况,目前尚不清楚:方法:我们利用开放存取的数据库研究了结肠癌中 PTX3 表达与成纤维细胞特征的关联。进行了功能缺失试验,包括他莫昔芬诱导的 Ptx3 基因敲除小鼠研究和抗 PTX3 中和抗体(WHC-001)治疗,以评估 PTX3 参与结肠癌进展的情况及其免疫抑制作用。最后,研究人员进行了生物信息学分析和体外实验,以揭示PTX3的下游效应因子,并解读CREB1/CEBPB轴参与PTX3反应和PTX3诱导的M2巨噬细胞极化促进作用:在临床上,PTX3的高表达与成纤维细胞和炎症反应特征呈正相关,并与结肠癌患者的不良生存结果有关。阻断 PTX3 能明显减少基质细胞介导的肿瘤发生。在异体移植的结肠肿瘤中,观察到 PTX3 失活后 M2 巨噬细胞数量减少,细胞毒性 CD8+ T 细胞数量增加。我们进一步发现,环磷酸腺苷反应元件结合蛋白1(CREB1)的激活介导了PTX3诱导的M2巨噬细胞极化的促进作用:结论:PTX3通过增加M2样巨噬细胞的极化来促进基质细胞介导的原肿瘤免疫,用WHC-001抑制PTX3是一种潜在的结肠癌治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信