Tumor cells promote immunosuppression in ovarian cancer via a positive feedback loop with MDSCs through the SAA1-IL-1β axis.

IF 12.8 1区 医学 Q1 ONCOLOGY
Haoran Hu, Meiqin Yang, Baoyou Huang, Jianyi Ding, Yashi Zhu, Xinxin Xu, Bo Yin, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Ang Li, Wei Wang, Lingfei Han
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引用次数: 0

Abstract

Background: Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood.

Methods: We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models.

Results: MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival.

Conclusion: This study uncovers a novel SAA1-IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor-immune interactions and suggest a potential biomarker and therapeutic target for EOC.

肿瘤细胞通过SAA1-IL-1β轴与MDSCs形成正反馈回路,促进卵巢癌的免疫抑制。
背景:上皮性卵巢癌(EOC)的免疫耐受使癌细胞能够逃避免疫监视。髓源性抑制细胞(MDSCs)作为重要的免疫抑制调节因子,塑造肿瘤微环境并有助于抵抗免疫治疗。然而,MDSCs在卵巢癌中的调控机制仍然知之甚少。方法:我们检测了骨髓间充质干细胞在EOC患者外周血和肿瘤组织中的存在和分布。对与MDSCs共培养的卵巢癌细胞进行转录组学分析。通过体外功能测定、共培养实验和小鼠体内模型研究血清淀粉样蛋白A1 (SAA1)的作用。结果:骨髓间充质干细胞在EOC患者外周血和肿瘤组织中均有富集。与MDSCs相互作用后,SAA1在卵巢癌细胞中显著上调,并在肿瘤样本和细胞系中得到证实。功能上,SAA1促进癌细胞增殖、迁移和侵袭。它还通过TLR2/4募集MDSCs,诱导粒细胞-单核细胞祖细胞(GMPs)分化,刺激IL-1β分泌,进而增强SAA1的表达,形成一个正反馈回路。在体内,SAA1促进肿瘤进展和腹水形成。临床上,高水平的SAA1、IL-1β和CD33 + MDSCs与较差的生存率相关。结论:本研究揭示了一种新的SAA1-IL-1β反馈回路促进卵巢癌的免疫抑制和进展。这些发现为肿瘤免疫相互作用提供了见解,并提出了EOC的潜在生物标志物和治疗靶点。
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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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