Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata 700019, India.
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
J Immunol. 2019 Dec 15;203(12):3447-3460. doi: 10.4049/jimmunol.1900692. Epub 2019 Nov 8.
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-β, 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.
肿瘤相关巨噬细胞是恶性进展和免疫治疗耐药的主要贡献者，但调节其从未成熟髓样前体分化的机制仍不完全清楚。在这项研究中，我们证明了人类和小鼠肿瘤诱导的间充质干细胞（MSC）分泌的外泌体通过诱导单核细胞髓样来源的抑制细胞分化为高度免疫抑制的 M2 极化巨噬细胞，在肿瘤部位加速乳腺癌的进展。从机制上讲，MSC 衍生的外泌体而不是肿瘤细胞衍生的外泌体含有 TGF-β、C1q 和 semaphorins，通过在未成熟的髓样单核前体和已分化的 CD206 巨噬细胞中过表达 PD-L1，并通过诱导 MHC 类 II 巨噬细胞分化，增强 l-精氨酸酶活性和 IL-10 分泌，在肿瘤部位发挥髓样耐受活性。因此，肿瘤相关的鼠 MSC 衍生的外泌体的给药通过抑制抗肿瘤免疫来加速肿瘤生长，而巨噬细胞耗竭消除了恶性进展中外泌体依赖性差异。我们的结果揭示了 MSC 衍生的外泌体在髓样来源的抑制细胞向巨噬细胞分化中的新作用，从而控制恶性生长。
