乳腺癌exosome诱导并调控CD73+γδ2Treg细胞及其分子机制研究

Breast cancer remains as the most popular malignant disease in women, and its initiation, relapse and metastasis believed closely related with inflammation and immune microenvironment. Recently research revealed γδT cells were the main subpopulation of tumor infiltration lymphocytes in breast cancer, therefore illuminate the function and differentiation mechanism of γδT cells could be the core part of breast cancer therapy. Our group firstly found CD73+γδ2T cells possessed strong immune suppressive function and its number was positively associated with tumor burden; besides, the breast cancer derived exosome could upregulate CD73 expression in γδ2T cells. However, the biological function of γδ2T cells in breast cancer and especially how it affected by breast cancer derived exosome still remained unclear. Based on the above achievement, firstly we identify the function of breast cancer derived exosome on γδ2T cells both in vivo with IVIS Lumina Imaging system, then screen and clarify the key molecular within exosome that potentiating the CD73 expression in γδ2T cells by iTRAQ assay, finally explore the clinical significance of CD73+γδ2T cells and the key molecular within exosome. This study will enrich the breast cancer-immune microenvironment theory and lay a solid foundation for discovery and development of related drugs.

乳腺癌是全球女性最常见的恶性肿瘤，其发生、复发转移均与肿瘤免疫微环境存在密切联系。近年来发现γδT细胞是乳腺癌浸润淋巴细胞的主要成分，因此研究该群细胞的功能与分化机制将为治疗乳腺癌提供有力帮助。目前对乳腺癌浸润γδT细胞的功能亚群及肿瘤来源exosome在免疫微环境中发挥何种作用知之甚少。我们前期研究首次发现乳腺癌浸润CD73+γδ2T细胞具有显著的免疫抑制能力，同时其数量与乳腺癌瘤负荷水平密切相关；此外，乳腺癌来源exosome可诱导γδ2T细胞CD73表达升高。本课题拟在前期工作基础上，通过小鼠活体成像技术及移植瘤模型明确exosome促进γδ2T细胞CD73的表达，利用iTRAQ技术鉴定exosome中调控γδ2T细胞CD73表达的关键分子，并分析CD73+γδ2T细胞及关键分子的临床生物学意义，由此探讨两者作为乳腺癌治疗靶点的可能性，为丰富肿瘤免疫微环境理论及开发相关药物提供依据。

乳腺癌是全球女性最常见的恶性肿瘤，其发生、复发转移均与肿瘤免疫微环境存在密切联 系。近年来发现γδT细胞是乳腺癌浸润淋巴细胞的主要成分，然而目前对乳腺癌浸润γδT细胞的功能亚群及肿瘤来源exosome在免疫微环境中调控机制知之甚少。我们研究首次发现乳腺癌局部CD73+γδ2T 细胞明显比例升高，且具有显著的免疫抑制能力，同时其数量与乳腺癌瘤负荷水平密切相关；此外，乳腺癌来源 exosome通过long non-coding RNA ZFAS1通过竞争性抑制miRNA-150促进sp1的表达，诱导γδ2T细胞CD73的表达升高。本研究系统性的阐述了乳腺癌CD73+γδT2细胞局部的免疫调控机制，为靶向CD73治疗乳腺癌提供了一定的临床依据。