Giovanna Talarico, Mara Lecchi, Anna Zanichelli, Paola Portararo, Laura Botti, Vera Cappelletti, Massimo Costanza, Annamaria Piva, Pietro Pratesi, Francesco Bertolini, Massimo Di Nicola, Claudio Tripodo, Valeria Cancila, Serenella Maria Pupa, Mario Paolo Colombo, Claudia Chiodoni, Paolo Verderio, Sabina Sangaletti
{"title":"ecm诱导的IL-23通过调节Tregs上的PD-1驱动乳腺癌免疫抑制。","authors":"Giovanna Talarico, Mara Lecchi, Anna Zanichelli, Paola Portararo, Laura Botti, Vera Cappelletti, Massimo Costanza, Annamaria Piva, Pietro Pratesi, Francesco Bertolini, Massimo Di Nicola, Claudio Tripodo, Valeria Cancila, Serenella Maria Pupa, Mario Paolo Colombo, Claudia Chiodoni, Paolo Verderio, Sabina Sangaletti","doi":"10.1186/s13046-025-03518-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs).</p><p><strong>Methods: </strong>In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature.</p><p><strong>Results: </strong>We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.</p><p><strong>Conclusion: </strong>These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"264"},"PeriodicalIF":12.8000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400771/pdf/","citationCount":"0","resultStr":"{\"title\":\"ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.\",\"authors\":\"Giovanna Talarico, Mara Lecchi, Anna Zanichelli, Paola Portararo, Laura Botti, Vera Cappelletti, Massimo Costanza, Annamaria Piva, Pietro Pratesi, Francesco Bertolini, Massimo Di Nicola, Claudio Tripodo, Valeria Cancila, Serenella Maria Pupa, Mario Paolo Colombo, Claudia Chiodoni, Paolo Verderio, Sabina Sangaletti\",\"doi\":\"10.1186/s13046-025-03518-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs).</p><p><strong>Methods: </strong>In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature.</p><p><strong>Results: </strong>We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.</p><p><strong>Conclusion: </strong>These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.</p>\",\"PeriodicalId\":50199,\"journal\":{\"name\":\"Journal of Experimental & Clinical Cancer Research\",\"volume\":\"44 1\",\"pages\":\"264\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400771/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental & Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13046-025-03518-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03518-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.
Background: High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs).
Methods: In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature.
Results: We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.
Conclusion: These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.
期刊介绍:
The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications.
We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options.
We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us.
We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community.
By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.