通过空间转录组学和血浆蛋白质组学识别与胃癌抗PD-1/PD-L1+抗血管生成原发性耐药性相关的微环境特征

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-09-13 DOI:10.1186/s12943-024-02092-x
Sophie Cousin, Jean-Philippe Guégan, Kohei Shitara, Lola Jade Palmieri, Jean Philippe Metges, Simon Pernot, Shota Fukuoka, Shohei Koyama, Hiroyoshi Nishikawa, Carine A. Bellera, Antoine Adenis, Carlos A. Gomez-Roca, Philippe Alexandre Cassier, Antoine Hollebecque, Coralie Cantarel, Michèle Kind, Isabelle Soubeyran, Lucile Vanhersecke, Alban Bessede, Antoine Italiano
{"title":"通过空间转录组学和血浆蛋白质组学识别与胃癌抗PD-1/PD-L1+抗血管生成原发性耐药性相关的微环境特征","authors":"Sophie Cousin, Jean-Philippe Guégan, Kohei Shitara, Lola Jade Palmieri, Jean Philippe Metges, Simon Pernot, Shota Fukuoka, Shohei Koyama, Hiroyoshi Nishikawa, Carine A. Bellera, Antoine Adenis, Carlos A. Gomez-Roca, Philippe Alexandre Cassier, Antoine Hollebecque, Coralie Cantarel, Michèle Kind, Isabelle Soubeyran, Lucile Vanhersecke, Alban Bessede, Antoine Italiano","doi":"10.1186/s12943-024-02092-x","DOIUrl":null,"url":null,"abstract":"Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":27.7000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of microenvironment features associated with primary resistance to anti-PD-1/PD-L1 + antiangiogenesis in gastric cancer through spatial transcriptomics and plasma proteomics\",\"authors\":\"Sophie Cousin, Jean-Philippe Guégan, Kohei Shitara, Lola Jade Palmieri, Jean Philippe Metges, Simon Pernot, Shota Fukuoka, Shohei Koyama, Hiroyoshi Nishikawa, Carine A. Bellera, Antoine Adenis, Carlos A. Gomez-Roca, Philippe Alexandre Cassier, Antoine Hollebecque, Coralie Cantarel, Michèle Kind, Isabelle Soubeyran, Lucile Vanhersecke, Alban Bessede, Antoine Italiano\",\"doi\":\"10.1186/s12943-024-02092-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.\",\"PeriodicalId\":19000,\"journal\":{\"name\":\"Molecular Cancer\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-09-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12943-024-02092-x\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12943-024-02092-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

抗血管生成药物在肿瘤微环境中会产生相当大的免疫调节作用,这就强调了在晚期胃癌(AGC)中协同开发血管内皮生长因子和免疫检查点抑制剂的临床合理性。涉及亚洲患者的早期研究显示了令人鼓舞的抗肿瘤疗效。我们报告了 REGOMUNE II 期研究的结果,在这项研究中,高加索患者接受了瑞戈非尼(一种多酪氨酸激酶抑制剂)与阿维列单抗(一种 PD-L1 靶向单克隆抗体)联合治疗。这一治疗方案使 19% 的患者获得了深度和持久的应答,但中位应答持续时间尚未达到。尽管如此,仍有相当一部分 AGC 患者没有表现出治疗优势,这促使人们对固有耐药机制进行研究。全面的生物标志物分析表明,无应答者主要表现为肿瘤微环境中 M2 巨噬细胞的增加,以及肿瘤细胞对 S100A10 的明显过度表达,而 S100A10 是一种以前被认为与巨噬细胞趋化有关的蛋白质。此外,外周生物标志物评估还发现,包括 CSF-1、IL-4、IL-8 和 TWEAK 在内的细胞因子水平升高与不良临床结果相关,从而突出了巨噬细胞浸润在介导抗药性方面的作用。这些见解为阐明并有可能规避当前 AGC 治疗范例中的耐药机制奠定了宝贵的基础,强调了肿瘤微环境动态和免疫调节的重要作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Identification of microenvironment features associated with primary resistance to anti-PD-1/PD-L1 + antiangiogenesis in gastric cancer through spatial transcriptomics and plasma proteomics
Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
期刊最新文献
SARS-CoV-2 nucleocapsid protein interaction with YBX1 displays oncolytic properties through PKM mRNA destabilization A prospective multi-cohort study identifies and validates a 5-gene peripheral blood signature predictive of immunotherapy response in non-small cell lung cancer Nanoparticles and bone microenvironment: a comprehensive review for malignant bone tumor diagnosis and treatment Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway. Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1