Ovarian cancer is largely diagnosed at advanced stages upon detection of multiple peritoneal dissemination, resulting in poor outcomes. CD47 is overexpressed in tumors, facilitates tumor immune evasion, and is located on exosomes. We aimed to investigate the role of exosomal CD47 in ovarian cancer progression. Prognostic significance of CD47 expression in ovarian cancer was examined using a public database including 1,435 patients and validated with 26 patients at our institution. CD47 expression was associated with poor progression-free survival and inversely correlated with macrophage infiltration in ovarian cancer tissues. Exosomes were collected from ovarian cancer cell lines, and CD47 expression on exosomes was confirmed via flow cytometry. Inhibition of exosome secretion with GW4869 and exosome uptake with 5-(N-ethyl-N-isopropyl)-amiloride inhibited the surface CD47 expression on ovarian cancer cells and promoted phagocytosis by macrophages. RAB27A (a key regulator of exosome release) knockdown inhibited exosome secretion and led to CD47 downregulation in ovarian cancer cells. In a xenograft mouse model, suppression of the release of tumor-derived exosomes by GW4869 or RAB27A knockdown suppressed tumor progression and enhanced M1 macrophage phagocytosis in cancer tissues. Collectively, CD47 expression was correlated with poor prognoses in patients with ovarian cancer, suggesting the importance of immune evasion. CD47 was expressed on exosomes and the inhibition of exosome secretion and/or uptake enhanced cancer cell phagocytosis by macrophages, and thus, suppressed peritoneal dissemination. This suggests the potential of a novel immune checkpoint therapeutic agent that focuses on exosomes. Implications: Mechanistic insight from the current study suggests that exosomal CD47 may be an advantageous therapeutic target in ovarian cancer.

中文翻译：

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外泌体 CD47 在卵巢癌的免疫逃避中发挥重要作用

在检测到多发性腹膜播散后，卵巢癌在很大程度上被诊断为晚期，导致结果不佳。CD47 在肿瘤中过度表达，有助于肿瘤免疫逃避，并位于外泌体上。我们旨在研究外泌体 CD47 在卵巢癌进展中的作用。使用包括 1,435 名患者的公共数据库检查了 CD47 表达在卵巢癌中的预后意义，并在我们机构的 26 名患者中进行了验证。CD47 表达与较差的无进展生存期相关，并且与卵巢癌组织中的巨噬细胞浸润呈负相关。从卵巢癌细胞系中收集外泌体，并通过流式细胞术确认外泌体上的 CD47 表达。用 GW4869 抑制外泌体分泌和用 5-(N-乙基-N-异丙基)-阿米洛利抑制外泌体吸收可抑制卵巢癌细胞表面 CD47 的表达并促进巨噬细胞的吞噬作用。RAB27A（外泌体释放的关键调节因子）敲低抑制了外泌体分泌并导致卵巢癌细胞中 CD47 下调。在异种移植小鼠模型中，通过 GW4869 或 RAB27A 敲低抑制肿瘤衍生外泌体的释放可抑制肿瘤进展并增强癌组织中的 M1 巨噬细胞吞噬作用。总的来说，CD47 表达与卵巢癌患者的不良预后相关，这表明免疫逃避的重要性。CD47 在外泌体上表达，抑制外泌体分泌和/或摄取会增强巨噬细胞对癌细胞的吞噬作用，因此，抑制腹膜播散。这表明了一种专注于外泌体的新型免疫检查点治疗剂的潜力。启示：目前研究的机制见解表明，外泌体 CD47 可能是卵巢癌的有利治疗靶点。