Macrophage-tumor chimeric exosomes accumulate in lymph node and tumor to activate the immune response and the tumor microenvironment
Menée à l'aide de lignées cellulaires, d'échantillons sanguins d'origine humaine et de xénogreffes de tumeurs sur des modèles murins, cette étude met en évidence l'intérêt d'une stratégie thérapeutique consistant à utiliser des macrophages activés de type M1 qui, après modification par introduction d'un noyau de cellules tumorales, produisent des exosomes chimériques capables de s'accumuler dans les ganglions lymphatiques et les tumeurs pour stimuler la réponse immunitaire
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.