Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
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DOI：
10.1172/jci40483
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发表时间：
2010-02-01
影响因子：
15.9
通讯作者：
Ghiringhelli, Francois
中科院分区：
文献类型：
--
作者：
Chalmin, Fanny;Ladoire, Sylvain;Ghiringhelli, Francois
骨髓源性抑制细胞 (MDSC) 在人类和小鼠中已被鉴定为一群未成熟的骨髓细胞，具有抑制 T 细胞活化的能力。它们在荷瘤小鼠和人类体内积累，并已被证明有助于癌症的发展。在这里，我们从小鼠细胞系中分离出肿瘤源性外泌体（TDE），并表明 TDE 相关的 Hsp72 和 MDSC 之间的相互作用通过激活 Stat3 来决定 MDSC 的抑制活性。此外，肿瘤来源的可溶性因子通过激活 Erk 触发 MDSC 扩增。 TDE 相关的 Hsp72 通过自分泌产生 IL-6，以 TLR2/MyD88 依赖性方式触发 MDSC 中 Stat3 的激活。重要的是，在 3 种不同的小鼠肿瘤模型中，使用二甲基阿米洛利减少外泌体的产生增强了化疗药物环磷酰胺的体内抗肿瘤功效。我们还证明了这种机制与癌症患者相关，因为来自人类肿瘤细胞系的 TDE 激活人类 MDSC，并以 Hsp72/TLR2 依赖性方式触发其抑制功能。此外，接受阿米洛利（一种用于治疗高血压、同时抑制外泌体形成的药物）治疗的癌症患者的 MDSC 表现出抑制功能降低。总的来说，我们的研究结果表明，在小鼠和人类中，TDE 表面表达的 Hsp72 通过促进 MDSC 抑制功能来抑制肿瘤免疫监视。
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.