Single-cell transcriptome analysis reveals the malignant characteristics of tumour cells and the immunosuppressive landscape in HER2-positive inflammatory breast cancer.

IF 12.8 1区 医学 Q1 ONCOLOGY
Juan Huang, Yongwei Zhu, Wenjing Zeng, Yulong Zhang, Weizhi Xia, Fan Xia, Liyu Liu, Kuansong Wang, Yidi Guan, Taohong Shen, Bingjian Jiang, Lunquan Sun, Ayong Cao, Shouman Wang, Zhi Li
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引用次数: 0

Abstract

Background: Inflammatory breast cancer (IBC), of which HER2 + is the predominant subtype, is extremely aggressive and difficult to treat. Previous studies have suggested that targeting the tumour microenvironment (TME) may provide new directions for IBC diagnosis and treatment.

Methods: In this study, we used single-cell transcriptome technology (scRNA-seq) to investigate the molecular features of the TME of HER2 + IBC patients and performed a comprehensive and detailed comparison of the cellular components and molecular phenotypes of the TME between IBC patients and noninflammatory breast cancer (nIBC) patients to elucidate the cell types that are specifically enriched in the TME of IBC patients, as well as the molecular features that are responsible for the preferential remodelling of the cellular functional state in the TME.

Results: A total of 15,832 cells, including epithelial cells, endothelial cells, stromal cells, T cells, B cells, antibody secreting cells (ASCs) and myeloid cells, were obtained from tumour tissues from 3 HER2 + IBC patients for scRNA analysis. By comparing the TME with that of HER2 + nIBC patients in a public database, we found that the TME of HER2 + IBC patients had a greater level of lymphocyte infiltration than that of nIBC patients did, and an especially significant enrichment of ASCs (mainly plasmablasts or plasma cells). In the TME of HER2 + IBC patients, tumour-infiltrating T cells exhibited a dual molecular phenotype of high activation and high exhaustion, with tumour-infiltrating B cells preferring the extrafollicular developmental pathway, and tumour-infiltrating myeloid and mesenchymal cells exhibiting a greater immunosuppressive status. By performing a cellular interaction analysis, we revealed that PTN molecules were significantly overexpressed in HER2 + IBC tumour cells and that the cellular interactions mediated by these molecules were strongly correlated with the functional polarisation of the cellular components in the TME. We observed that HER2 + IBC tumour cells have an active interferon response and epithelial mesenchymal transition (EMT) signalling, and that their malignant process is strongly correlated with the inflammatory response. Moreover, we found that HER2 + IBC tumour-infiltrating B cells promoted necroptosis of endothelial cells through high expression of TNF, thus promoting inflammatory responses.

Conclusion: We found a strong correlation between high expression of PTN molecules in HER2 + IBC tumour cells and their highly invasive characteristics and highly immunosuppressive TME. These results suggest that HER2 + IBC tumour cells can promote an inflammatory response by upregulating the expression of TNF molecules in B cells via PTN molecules and that the enhanced inflammatory response in turn promotes tumour progression, a malignant cycle that shapes a more immunosuppressive TME. Therefore, diagnostic and therapeutic strategies targeting the PTN-TNF molecular axis may have considerable potential for development in HER2 + IBC patients.

单细胞转录组分析揭示了her2阳性炎性乳腺癌肿瘤细胞的恶性特征和免疫抑制景观。
背景:炎症性乳腺癌(IBC)极具侵袭性且难以治疗,其中HER2 +是主要亚型。既往研究提示,靶向肿瘤微环境(tumor microenvironment, TME)可能为IBC的诊断和治疗提供新的方向。方法:在本研究中,我们利用单细胞转录组技术(scRNA-seq)研究了HER2 + IBC患者TME的分子特征,并对IBC患者和非炎症性乳腺癌(nIBC)患者TME的细胞成分和分子表型进行了全面、详细的比较,以阐明IBC患者TME中特异性富集的细胞类型。以及在TME中负责细胞功能状态优先重塑的分子特征。结果:从3例HER2 + IBC患者的肿瘤组织中共获得15832个细胞,包括上皮细胞、内皮细胞、基质细胞、T细胞、B细胞、抗体分泌细胞(ASCs)和骨髓细胞,用于scRNA分析。通过与公共数据库中HER2 + nIBC患者的TME比较,我们发现HER2 + IBC患者的TME淋巴细胞浸润水平高于nIBC患者,且ASCs(主要是浆母细胞或浆细胞)的富集尤为显著。在HER2 + IBC患者的TME中,肿瘤浸润T细胞表现出高激活和高耗损的双重分子表型,肿瘤浸润B细胞倾向于滤泡外发育途径,而肿瘤浸润骨髓和间充质细胞表现出更大的免疫抑制状态。通过细胞相互作用分析,我们发现PTN分子在HER2 + IBC肿瘤细胞中显着过表达,并且这些分子介导的细胞相互作用与TME中细胞成分的功能极化密切相关。我们观察到HER2 + IBC肿瘤细胞具有活跃的干扰素反应和上皮间充质转化(EMT)信号,并且它们的恶性过程与炎症反应密切相关。此外,我们发现HER2 + IBC肿瘤浸润性B细胞通过高表达TNF促进内皮细胞坏死,从而促进炎症反应。结论:我们发现PTN分子在HER2 + IBC肿瘤细胞中的高表达与其高侵袭性和高免疫抑制性TME有很强的相关性。这些结果表明,HER2 + IBC肿瘤细胞可以通过PTN分子上调B细胞中TNF分子的表达来促进炎症反应,并且增强的炎症反应反过来促进肿瘤进展,恶性循环形成更具免疫抑制性的TME。因此,针对PTN-TNF分子轴的诊断和治疗策略在HER2 + IBC患者中可能具有相当大的发展潜力。
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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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