Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2024-09-25 DOI:10.1111/cas.16348
Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike
{"title":"Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.","authors":"Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike","doi":"10.1111/cas.16348","DOIUrl":null,"url":null,"abstract":"<p><p>Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor \"immunophenotypes\" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cas.16348","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

Abstract

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

宿主 ANGPTL2 可建立免疫抑制性肿瘤微环境,并对免疫检查点疗法产生抗药性。
使用免疫检查点抑制剂(ICIs)作为癌症免疫疗法在临床上进展迅速;然而,ICI疗法的抗药性机制,包括T细胞浸润受损、免疫原性低以及受宿主控制的肿瘤 "免疫表型",仍不清楚。我们以前曾报道过,在某些癌症中,肿瘤细胞衍生的血管生成素样蛋白 2(ANGPTL2)具有促进肿瘤生长的功能。在此,我们探讨了 ANGPTL2 缺乏是否能在两种炎症环境中增强 ICI 的抗肿瘤活性:一种是结直肠癌小鼠合成模型,另一种是高脂饮食(HFD)诱导肥胖症小鼠模型。系统性 ANGPTL2 缺乏会增强 ICI 在合成模型中的疗效,从而支持宿主 ANGPTL2 的免疫抑制作用。与这一机制相关的是,我们发现 ANGPTL2 能诱导脂肪组织产生促炎细胞因子,推动骨髓中髓源性抑制细胞(MDSCs)的生成,并促成免疫抑制性肿瘤微环境和对 ICI 治疗的耐药性。此外,HFD诱导的肥胖小鼠对ICI治疗的反应性减弱,这表明ANGPTL2高表达导致的肥胖诱导的慢性炎症阻碍了ICI的抗肿瘤作用。我们的研究结果总体上提供了对原发肿瘤 ANGPTL2 功能的新见解,并说明了宿主系统在 ICI 反应性中的重要作用。
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
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
×
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