Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer
Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer
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DOI：
10.4049/jimmunol.1900692
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发表时间：
2019-12-15
影响因子：
4.4
通讯作者：
Bhattacharyya, Arindam
中科院分区：
文献类型：
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作者：
Biswas, Subir;Mandal, Gunjan;Bhattacharyya, Arindam
肿瘤相关巨噬细胞是恶性进展和免疫治疗抵抗的主要贡献者，但其从未成熟骨髓前体分化的机制仍不完全清楚。在这项研究中，我们证明了由人类和小鼠肿瘤训练的间充质干细胞（MSC）分泌的外泌体通过诱导单核细胞骨髓源性抑制细胞分化为肿瘤床上高度免疫抑制的M2极化巨噬细胞来加速乳腺癌的进展。从机制上讲，MSC来源的外泌体（而不是来自肿瘤细胞的外泌体）含有TGF-β、C1 q和脑信号蛋白，这些蛋白通过驱动未成熟骨髓单核细胞前体和定向CD 206（+）巨噬细胞中的PD-L1过表达，以及通过诱导MHC II类+巨噬细胞分化，增强肿瘤床的L-精氨酸酶活性和IL-10分泌，从而促进骨髓耐受原活性。因此，施用肿瘤相关的鼠MSC衍生的外泌体通过抑制抗肿瘤免疫而加速肿瘤生长，并且巨噬细胞消耗消除了恶性进展中的外泌体依赖性差异。我们的研究结果揭示了MSC衍生的外泌体在髓源性抑制细胞分化为巨噬细胞中的新作用，巨噬细胞控制恶性生长。
Tumor-associated macrophages are major contributors to malignant progression and resistance to immunotherapy, but the mechanisms governing their differentiation from immature myeloid precursors remain incompletely understood. In this study, we demonstrate that exosomes secreted by human and mouse tumor-educated mesenchymal stem cells (MSCs) drive accelerated breast cancer progression by inducing differentiation of monocytic myeloid-derived suppressor cells into highly immunosuppressive M2-polarized macrophages at tumor beds. Mechanistically, MSC-derived exosomes but not exosomes from tumor cells contain TGF-beta, C1q, and semaphorins, which promote myeloid tolerogenic activity by driving PD-L1 overexpression in both immature myelomonocytic precursors and committed CD206(+) macrophages and by inducing differentiation of MHC class II+ macrophages with enhanced L-Arginase activity and IL-10 secretion at tumor beds. Accordingly, administration of tumor-associated murine MSC-derived exosomes accelerates tumor growth by dampening antitumor immunity, and macrophage depletion eliminates exosome-dependent differences in malignant progression. Our results unveil a new role for MSC-derived exosomes in the differentiation of myeloid-derived suppressor cells into macrophages, which governs malignant growth.