ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.

IF 12.8 1区 医学 Q1 ONCOLOGY
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
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引用次数: 0

Abstract

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.

Abstract Image

Abstract Image

Abstract Image

ecm诱导的IL-23通过调节Tregs上的PD-1驱动乳腺癌免疫抑制。
背景:高级别乳腺癌(HGBC)是一种预后不良的侵袭性疾病,需要新的治疗策略。肿瘤微环境(TME),特别是细胞外基质(ECM),在肿瘤进展、治疗抵抗和免疫调节中起着关键作用。在大约35%的HGBC病例中发现的ecm相关基因标记(定义为ECM3)与侵袭性肿瘤、上皮-间质转化(EMT)、不良临床结果和免疫抑制性骨髓源性抑制细胞(MDSCs)浸润增加有关。方法:在本研究中,我们研究了ECM对HGBC患者T细胞调节的影响,重点关注ECM3 +肿瘤与T细胞表型的关系。我们使用小鼠模型来剖析将ECM成分与T细胞调节联系起来的分子机制,特别关注基质细胞蛋白SPARC的作用,SPARC是ECM3特征的关键成分。结果:我们揭示了高度抑制性程序性细胞死亡-1 (PD-1)负调节性T细胞(Tregs)与ECM3 +肿瘤之间的显著相关性。在小鼠模型中,我们发现SPARC通过促进IL-23的释放来下调Tregs上的PD-1,从而诱导pdcd1基因的抑制因子SATB1的表达。IL-23受体在Tregs上的选择性表达解释了IL-23对这些细胞的靶向作用。值得注意的是,用单克隆抗体阻断IL-23可以恢复Tregs上PD-1的表达并激活T效应细胞。结论:这些发现将ECM的免疫调节作用扩展到包括调节性T细胞,并确定了高级别乳腺癌的潜在新治疗靶点。此外,他们强调ECM3是对PD-1/PD-L1免疫检查点阻断(ICB)耐药的潜在生物标志物,这表明ECM3 +患者可能受益于PD-1/PD-L1以外的其他检查点抑制剂治疗。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
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.
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