PO.TB10.15 · 肿瘤生物学

脂肪肉瘤来源的细胞外囊泡抑制 STING 信号传导并损害巨噬细胞的固有免疫激活

Liposarcoma-derived extracellular vesicles suppress STING signaling and impair innate immune activation in macrophages

编号 3348 展板 9 时间 4/20 02:00–05:00 区域 Section 26 主讲 Qi Zhang, MD

分会场 Extracellular Vesicles and Long-Range Tumor-Host Communication

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作者与单位 Authors & Affiliations

Qi Zhang, Patricia Sarchet, Fernanda C. C. de Faria, Priya Dhawale, Sydney Rentsch, Roma Karna, Valerie Grignol, Jing Wang, Raphael Pollock, Federica Calore

The Ohio State University Comprehensive Cancer Center, Columbus, OH

摘要 Abstract

中文摘要

目的：巨噬细胞是脂肪肉瘤肿瘤微环境（TME）中最丰富的免疫细胞群。我们此前表明，去分化脂肪肉瘤（DDLPS）释放的细胞外囊泡（EV）通过诱导巨噬细胞分泌 IL6 来促进肿瘤进展。在此，我们研究了 DDLPS 来源的 EV 是否也破坏巨噬细胞的固有免疫信号传导。方法：用 PMA 将 U937 细胞分化为巨噬细胞。使用 M-CSF 将从 PBMC 中分离的 CD14+ 单核细胞分化为单核细胞来源的巨噬细胞（MDM），并通过流式细胞术确认巨噬细胞身份。通过超速离心从 Lipo141 和 Lipo246 条件培养基中分离 EV，并使用 ExoQuick 从患者血清中分离 EV。将分化的巨噬细胞用 EV 处理 24 小时，随后进行 cGAMP 刺激。通过 qRT-PCR 评估 ifnb1 和固有免疫相关趋化因子的基因表达，同时通过 ELISA 实验测定 IFNbeta 分泌。通过 Western blot 分析研究 STING 通路激活。结果：DDLPS 来源的 EV 显著抑制了巨噬细胞对 cGAMP 的反应。在 U937 来源的巨噬细胞中，EV 暴露显著降低了 cGAMP 诱导的 ifnb1 诱导（p=0.044）和 IFNbeta 分泌。从健康供体或 DDLPS 患者（n=12）血清中分离的 EV 证实了这些发现，与健康供体组相比，患者来源的 EV 导致 ifnb1 的更强抑制（p=0.0012）以及 IFNbeta 蛋白水平降低。Western blot 分析显示 IRF3 和 STING 的磷酸化降低，而总蛋白水平不变，表明 STING 通路激活的选择性受损。与这些数据一致，MDM 表现出类似的功能抑制：EV 处理的细胞在 cGAMP 刺激下显示出 ccl5、cxcl9、cxcl10、ifnb1 和 ISG15 诱导的减少。结论：DDLPS 来源的 EV 通过抑制 STING 通路激活损害了巨噬细胞对 cGAMP 的反应性。这些发现揭示了脂肪肉瘤中一种 EV 介导的免疫逃逸机制，并强调 STING 轴作为恢复抗肿瘤免疫功能的潜在治疗靶点。

查看英文原文 English abstract

Purpose: Macrophages are the most abundant immune population in the liposarcoma tumor microenvironment (TME). We previously showed that extracellular vesicles (EVs) released by de-differentiated liposarcoma (DDLPS) promote tumor progression by inducing IL6 secretion from macrophages. Here, we investigated whether DDLPS-derived EVs also disrupt macrophages innate immune signaling. Methods: U937 cells were differentiated into macrophages with PMA. CD14+ monocytes isolated from PBMCs were differentiated into monocyte-derived macrophages (MDMs) using M-CSF, and macrophage identity was confirmed by flow cytometry. EVs were isolated from Lipo141 and Lipo246 conditioned medium via ultracentrifugation, and from patient serum using ExoQuick. Differentiated macrophages were treated with EVs for 24h, followed by cGAMP stimulation. Gene expression of ifnb1 and innate immunity-related chemokines were assessed by qRT-PCR, while IFNbeta secretion was determined by ELISA assay. STING pathway activation was investigated by western blot analysis. Results: DDLPS-derived EVs markedly suppressed macrophage responses to cGAMP. In U937-derived macrophages, EVs exposure significantly reduced ifnb1 induction (p=0.044) and IFNbeta secretion in response to cGAMP. EVs isolated from the serum of healthy donors or DDLPS patients (n=12) confirmed these findings, with patient-derived EVs leading to a stronger inhibition of ifnb1 (p=0.0012) and reduced IFNbeta protein levels compared to healthy donor group. Western blot analysis showed decreased phosphorylation of IRF3 and STING, with total protein levels unchanged, indicating selective impairment of STING pathway activation. Consistent with these data, MDMs exhibited similar functional suppression: EV-treated cells displayed reduced induction of ccl5, cxcl9, cxcl10, ifnb1 and ISG15 in response to cGAMP stimulation. Conclusion: DDLPS-derived EVs impair macrophage responsiveness to cGAMP by suppressing STING pathway activation. These findings reveal an EV-mediated mechanism of immune evasion in liposarcoma and highlight the STING axis as a potential therapeutic target to restore antitumor immune function.

利益披露 Disclosure

Q. Zhang, None.. P. Sarchet, None.. F. C. C. de Faria, None.. P. Dhawale, None.. S. Rentsch, None.. R. Karna, None.. V. Grignol, None.. J. Wang, None.. R. Pollock, None.. F. Calore, None.

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