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.

中文翻译：

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巨噬细胞-肿瘤嵌合外泌体在淋巴结和肿瘤中积累以激活免疫反应和肿瘤微环境

尽管有多种免疫治疗技术可以实现有效的 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。受近期纳米级分泌囊泡（称为外泌体）作为治疗剂的进展以及研究表明循环癌细胞具有“归巢”能力返回主要肿瘤部位的启发，我们产生了巨噬细胞-肿瘤杂交细胞。我们将从肿瘤细胞中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多种肿瘤中积累。它们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”方式进入淋巴结并引发 T 细胞活化。aMT-exos 对肿瘤部位也有很强的“归巢行为”，它们改善了免疫抑制。它们在淋巴瘤、乳腺癌和黑色素瘤的原发性小鼠模型中有效诱导肿瘤消退和延长生存期。此外，当与抗程序性死亡 1 (a-PD1) 治疗相结合时，aMT-exos 能够延长转移性和术后肿瘤复发小鼠模型的生存期。这种免疫反应和肿瘤微环境的共激活使 aMT-exos 能够有效抑制原发性肿瘤、肿瘤转移和术后肿瘤复发，从而实现个性化免疫治疗，