Macrophage-tumor chimeric exosomes accumulate in lymph node and tumor to activate the immune response and the tumor microenvironment
Macrophage-tumor chimeric exosomes accumulate in lymph node and tumor to activate the immune response and the tumor microenvironment
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DOI：
10.1126/scitranslmed.abb6981
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发表时间：
2021-10-13
影响因子：
17.1
通讯作者：
Ma, Guanghui
中科院分区：
文献类型：
--
作者：
Wang, Shuang;Li, Feng;Ma, Guanghui
尽管多种免疫抑制技术实现了有效的T细胞活化，但由于肿瘤微环境中的高度免疫抑制条件，效应T细胞仍然缺乏效率。受纳米大小的分泌囊泡（称为外泌体）作为治疗剂的最新进展以及研究揭示循环癌细胞具有返回主要肿瘤部位的“归巢”能力的启发，我们产生了巨噬细胞-肿瘤杂交细胞。我们将从肿瘤细胞分离的细胞核引入活化的M1样巨噬细胞中以产生嵌合外泌体（aMT-exos）。aMT-exos能够在异种移植小鼠的淋巴结和各种肿瘤中积累。它们进入淋巴结并以经典的抗原呈递细胞诱导的免疫刺激方式和独特的“直接外泌体相互作用“方式引发T细胞活化。aMT-exos还具有对肿瘤部位的强“归巢行为”，在那里它们改善免疫抑制。它们在诱导肿瘤消退和延长淋巴瘤、乳腺癌和黑色素瘤原发小鼠模型的存活期方面是有效的。此外，当与抗程序性死亡1（a-PD 1）治疗组合时，aMT-exos能够延长转移性和术后肿瘤复发小鼠模型的存活。免疫应答和肿瘤微环境的这种共激活使得aMT-exos能够有效抑制原发性肿瘤、肿瘤转移和术后肿瘤复发，用于个性化免疫治疗，这需要在临床环境中进一步探索。
Despite multiple immunotherapeutic technologies that achieve potent T cell activation, effector T cells still lack efficiency because of the highly immunosuppressive conditions in the tumor microenvironment. Inspired by recent advances in nano-sized secreted vesicles known as exosomes as therapeutic agents and research revealing that circulating cancer cells have a "homing" capacity to return to the main tumor sites, we generated macrophage-tumor hybrid cells. We introduced nuclei isolated from tumor cells into activated M1-like macrophages to produce chimeric exosomes (aMT-exos). The aMT-exos were able to accumulate in both lymph nodes and diverse tumors of xenograft mice. They entered lymph nodes and primed T cell activation in both the classical antigen-presenting cell-induced immunostimulatory manner and a unique "direct exosome interaction"manner. aMT-exos also had strong "homing behavior" to tumor sites, where they ameliorated immunosuppression. They were effective in inducing tumor regression and extending survival in primary mouse models of lymphoma and breast and melanoma cancers. In addition, when combined with anti-programmed death 1 (a-PD1) treatment, aMT-exos were able to extend survival of metastatic and postsurgical tumor recurrence mouse models. Such a coactivation of the immune response and the tumor microenvironment enabled aMT-exos to confer efficient inhibition of primary tumors, tumor metastases, and postoperative tumor recurrence for personalized immunotherapy, which warrants further exploration in the clinical setting.