Adipose stem cell exosomes, stimulated by pro-inflammatory factors, enhance immune evasion in triple-negative breast cancer by modulating the HDAC6/STAT3/PD-L1 pathway through the transporter UCHL1.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2024-11-20 DOI:10.1186/s12935-024-03557-1

Qin Zhu, Kejing Zhang, Yukun Cao, Yu Hu

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引用次数: 0

Abstract

Background: Triple-negative breast cancer (TNBC) is characterized by high invasiveness and metastasis potential. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is strongly associated with breast cancer progression, although the underlying mechanisms are largely unknown.

Methods: The gene expression profiles of TNBC samples were downloaded from the TCGA database, and ubiquitination enzymes related to immune regulation were screened. UCHL1 expression in the TNBC tissues and in adipose-derived mesenchymal stem cells (ADSCs) stimulated in vitro with pro-inflammatory cytokines were analyzed. Exosomes were isolated from these stimulated ADSCs and transfected with scrambled (si-NC) or UCHL1-specific (si-UCHL1) siRNA constructs. TNBC cells were treated with the ADSCs-derived exosomes (ADSCs-Exos) and then co-cultured with macrophages or T cells. Finally, the tumorigenic potential of the ADSCs-Exos was evaluated by injecting the exosomes into mice bearing TNBC xenografts.

Results: UCHL1 was highly expressed in TNBC tissues and the stimulated ADSCs. The exosomes derived from stimulated ADSCs increased the viability and migration capacity of TNBC cells in vitro, and significantly increased Ki-67 expression through UCHL1. Furthermore, ADSCs-Exos induced M2 polarization of THP-1 monocytes by upregulating CD206 and Arg-1, and downregulating TNF-α and iNOS, and also decreased the proportion of CD3⁺CD8⁺ T cells. Mechanistically, UCHL1 regulated the STAT3 and PD-L1 signaling pathways through HDAC6. Exosomes derived from the control and cytokine-stimulated ADSCs also promoted tumor growth in vivo, and increased the expression of UCHL1, CD206, HDAC6, STAT3, and PD-L1. However, UCHL1 knockdown reversed the pro-tumorigenic effects of the ADSCs-derived exosomes in vivo and in vitro.

Conclusion: Pro-inflammatory factors (IFN-γ + TNF-α) stimulating ADSCs-Exos enhance immune evasion in triple-negative breast cancer by regulating the HDAC6/STAT3/PD-L1 pathway via UCHL1 transporter. Thus, UCHL1 inhibition may enhance the response of TNBC to immunotherapy.

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脂肪干细胞外泌体在促炎因子的刺激下，通过转运体UCHL1调节HDAC6/STAT3/PD-L1途径，增强三阴性乳腺癌的免疫逃避能力。

背景：三阴性乳腺癌（TNBC三阴性乳腺癌（TNBC）的特点是高侵袭性和高转移潜力。泛素羧基末端水解酶 L1（UCHL1）与乳腺癌的进展密切相关，但其潜在机制尚不清楚：方法：从TCGA数据库下载TNBC样本的基因表达谱，筛选与免疫调节相关的泛素化酶。方法：从TCGA数据库下载了TNBC样本的基因表达谱，并筛选了与免疫调节相关的泛素化酶，分析了UCHL1在TNBC组织中的表达，以及在体外用促炎细胞因子刺激的脂肪间充质干细胞（ADSCs）中的表达。从这些受刺激的 ADSCs 中分离出外泌体，并用乱码（si-NC）或 UCHL1 特异性（si-UCHL1）siRNA 构建物进行转染。用 ADSCs 衍生的外泌体（ADSCs-Exos）处理 TNBC 细胞，然后与巨噬细胞或 T 细胞共同培养。最后，将外泌体注射到TNBC异种移植小鼠体内，评估ADSCs-Exos的致瘤潜力：结果：UCHL1在TNBC组织和受刺激的ADSCs中高表达。结果：UCHL1在TNBC组织和受刺激的ADSCs中高表达，受刺激的ADSCs外泌体提高了TNBC细胞在体外的存活率和迁移能力，并通过UCHL1显著增加了Ki-67的表达。此外，ADSCs-外泌体通过上调CD206和Arg-1、下调TNF-α和iNOS诱导THP-1单核细胞的M2极化，并降低CD3+CD8+T细胞的比例。从机制上讲，UCHL1通过HDAC6调控STAT3和PD-L1信号通路。从对照组和细胞因子刺激的 ADSCs 提取的外泌体也促进了体内肿瘤的生长，并增加了 UCHL1、CD206、HDAC6、STAT3 和 PD-L1 的表达。然而，UCHL1的敲除逆转了ADSCs衍生的外泌体在体内和体外的促肿瘤作用：结论：刺激 ADSCs-Exos 的促炎因子（IFN-γ + TNF-α）通过 UCHL1 转运体调节 HDAC6/STAT3/PD-L1 通路，增强了三阴性乳腺癌的免疫逃避能力。因此，抑制 UCHL1 可增强 TNBC 对免疫疗法的反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.