【科技前瞻】Cancer Immunol Res：外泌体为治疗上皮性卵巢癌提供干预靶点

生物_医药_科研 2019-02-02

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上皮性卵巢癌（epithelial ovarian cancer，EOC）是妇科癌症相关死亡的最常见原因，其特征在于高复发率和有效治疗的缺乏。与其他实体肿瘤不同的是，EOC细胞通过形成许多结节转移到腹膜腔，腹膜中存在免疫抑制微环境，进一步加剧了肿瘤进展。研究表明，EOC患者的腹膜含有丰富的免疫细胞，其中70％是肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs），25％是T细胞。TAM可通过分泌IL-10来增加调节性T细胞（Tregs）来促进肿瘤进展，提示靶向肿瘤相关免疫细胞之间的关联机制和免疫抑制性微环境可能是用于EOC治疗有效的策略。

近日，来自上海交通大学医学院附属新华医院的汪希鹏课题组发现，肿瘤相关巨噬细胞衍生的外泌体可转移miRNA，包括miR-29a-3p和miR-21-5p，通过直接靶向CD4⁺T细胞中的STAT3协同诱导Treg/ Th17细胞失衡。TAMs是肿瘤微环境中的免疫细胞最多的类型，并在肿瘤生长、侵袭、血管生成和转移中发挥重要作用，TAM也影响卵巢癌患者的长期预后。TAM能够产生外泌体，将生物材料传递到微环境中的相邻细胞里。在该研究中，原位和转移性腹膜EOC组织中的Treg/ Th17比例显著高于良性卵巢肿瘤和良性腹膜组织。Treg/ Th17比例与组织学分级相关，并且是EOC患者总体存活的独立预后因素。在源自TAM的外泌体微阵列分析的基础上，研究人员鉴定了在外泌体中富集的miRNA，包括miR-29a-3p和miR-21-5p。这两个miRNA模拟物转染到CD4⁺T细胞中时，直接抑制STAT3并调节Treg/ Th17比例，并且Treg/ Th17比例对STAT3抑制具有协同作用。

这些结果表明外泌体介导TAM和T细胞之间的相互作用，进而影响EOC进展的免疫抑制微环境，而靶向这些外泌体或其相关的miRNA可能为开发EOC治疗新方法提供新途径。

推荐阅读原文：
Exosomes released from tumor-associated macrophages transfer miRNAs that induce a Treg/Th17 cell imbalance in epithelial ovarian cancer.
The immune microenvironment is crucial for epithelial ovarian cancer (EOC) progression and consists of tumor-associated macrophages (TAM) and T lymphocytes, such as regulatory T cells (Treg) and T helper 17 (Th17) cells. In this study, the Treg/Th17 ratio was significantly higher in EOC in situ and in metastatic peritoneal tissues than in benign ovarian tumors and benign peritoneum. The Treg/Th17 ratio was associated with histologic grade and was an independent prognostic factor for overall survival of EOC patients. On the basis of microarray analysis of exosomes derived from TAMs, we identified miRNAs enriched in the exosomes, including miR-29a-3p and miR-21-5p. When the two miRNA mimics were transfected into CD4⁺ T cells, they directly suppressed STAT3 and regulated Treg/Th17 cells, inducing an imbalance, and they had a synergistic effect on STAT3 inhibition. Taken together, these results indicate that exosomes mediate the interaction between TAMs and T cells, generating an immune-suppressive microenvironment that facilitates EOC progression and metastasis. These findings suggest that targeting these exosomes or their associated miRNAs might pave the way for the development of novel treatments for EOC.