骨髓来源的抑制性细胞(Myeloid-derived suppressor cells，MDSCs)是骨髓来源的一群异质性细胞，是树突状细胞(dendritic cells，DCs)、巨噬细胞和(或)粒细胞的前体，具有显著抑制免疫细胞应答的能力。在长有肿瘤的小鼠和人体内这类细胞增多，并促进了肿瘤的生长。
来自法国国家健康与医学研究院的研究人员们从小鼠细胞系培养上清中分离出肿瘤来源的外泌体（exosome）（tumor-derived exosomes, TDEs）,并发现外泌体（exosome）上的HSP72通过激活STAT3抑制了MDSCs的免疫抑制作用。另外，肿瘤来源的可溶性分子通过Erk激发了MDSCs的扩增。外泌体（exosome）HSP72通过TLR2/MyD88依赖的方式诱导IL-6的自分泌，从而激活STAT3。更重要的是，在3个不同的小鼠肿瘤模型中使用dimethyl amilorid抑制外泌体（exosome）的分泌可增强化疗药物cyclophosphamide的抗肿瘤效果。人肿瘤细胞系来源的外泌体（exosome）可激活MDSCs，从而激发其Hsp72/TLR2依赖的免疫抑制作用。用amiloride（一种高血压治疗药物，也可以抑制外泌体（exosome）的形成）处理肿瘤病人来源的MDSCs可降低其免疫抑制作用。
简言之，该工作发现肿瘤来源的外泌体（exosome）含有膜蛋白HSP72，促进MDSCs的免疫抑制功能，抑制了肿瘤的免疫监督。
Chalmin, F., et al. (2010). "Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells." J Clin Invest 120(2): 457-471. IF=13.2
Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
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