上皮性卵巢癌（epithelial ovarian cancer，EOC）是婦科癌癥相關(guān)死亡的最常見原因，其特征在于高復(fù)發(fā)率和有效治療的缺乏。與其他實(shí)體腫瘤不同的是，EOC細(xì)胞通過形成許多結(jié)節(jié)轉(zhuǎn)移到腹膜腔，腹膜中存在免疫抑制微環(huán)境，進(jìn)一步加劇了腫瘤進(jìn)展。研究表明，EOC患者的腹膜含有豐富的免疫細(xì)胞，其中70％是腫瘤相關(guān)巨噬細(xì)胞（tumor-associated macrophages，TAMs），25％是T細(xì)胞。TAM可通過分泌IL-10來增加調(diào)節(jié)性T細(xì)胞（Tregs）來促進(jìn)腫瘤進(jìn)展，提示靶向腫瘤相關(guān)免疫細(xì)胞之間的關(guān)聯(lián)機(jī)制和免疫抑制性微環(huán)境可能是用于EOC治療有效的策略。

近日，來自上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院的汪希鵬課題組發(fā)現(xiàn)，腫瘤相關(guān)巨噬細(xì)胞衍生的外泌體可轉(zhuǎn)移miRNA，包括miR-29a-3p和miR-21-5p，通過直接靶向CD4⁺T細(xì)胞中的STAT3協(xié)同誘導(dǎo)Treg/ Th17細(xì)胞失衡。TAMs是腫瘤微環(huán)境中的免疫細(xì)胞最多的類型，并在腫瘤生長、侵襲、血管生成和轉(zhuǎn)移中發(fā)揮重要作用，TAM也影響卵巢癌患者的長期預(yù)后。TAM能夠產(chǎn)生外泌體，將生物材料傳遞到微環(huán)境中的相鄰細(xì)胞里。在該研究中，原位和轉(zhuǎn)移性腹膜EOC組織中的Treg/ Th17比例顯著高于良性卵巢腫瘤和良性腹膜組織。Treg/ Th17比例與組織學(xué)分級(jí)相關(guān)，并且是EOC患者總體存活的獨(dú)立預(yù)后因素。在源自TAM的外泌體微陣列分析的基礎(chǔ)上，研究人員鑒定了在外泌體中富集的miRNA，包括miR-29a-3p和miR-21-5p。這兩個(gè)miRNA模擬物轉(zhuǎn)染到CD4⁺T細(xì)胞中時(shí)，直接抑制STAT3并調(diào)節(jié)Treg/ Th17比例，并且Treg/ Th17比例對(duì)STAT3抑制具有協(xié)同作用。

這些結(jié)果表明外泌體介導(dǎo)TAM和T細(xì)胞之間的相互作用，進(jìn)而影響EOC進(jìn)展的免疫抑制微環(huán)境，而靶向這些外泌體或其相關(guān)的miRNA可能為開發(fā)EOC治療新方法提供新途徑。

推薦閱讀原文：
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.