Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. Lu Zhen,Zuo Bingfeng,Jing Renwei,Gao Xianjun,Rao Quan,Liu Zhili,Qi Han,Guo Hongxing,Yin HaiFang Journal of hepatology BACKGROUND & AIMS:Dendritic cell (DC)-derived exosomes (DEXs) form a new class of vaccines for cancer immunotherapy. However, their potency in hepatocellular carcinoma (HCC), a life-threatening malignancy with limited treatment options in the clinic that responds poorly to immunotherapy, remains to be investigated. METHODS:Exosomes derived from α-fetoprotein (AFP)-expressing DCs (DEX) were investigated in three different HCC mouse models systemically. Tumor growth and microenvironment were monitored. RESULTS:DEX elicited strong antigen-specific immune responses and resulted in significant tumor growth retardation and prolonged survival rates in mice with ectopic, orthotopic and carcinogen-induced HCC tumors that displayed antigenic and pathological heterogeneity. The tumor microenvironment was improved in DEX-treated HCC mice, demonstrated by significantly more γ-interferon (IFN-γ)-expressing CD8 T lymphocytes, elevated levels of IFN-γ and interleukin-2, and fewer CD25Foxp3 regulatory T (Treg) cells and decreased levels of interleukin-10 and transforming growth factor-β in tumor sites. Lack of efficacy in athymic nude mice and CD8 T cell-depleted mice showed that T cells contribute to DEX-mediated antitumor function. Dynamic examination of the antitumor efficacy and the immune microenvironment in DEX-treated orthotopic HCC mice at different time-points revealed a positive correlation between tumor suppression and immune microenvironment. CONCLUSIONS:Our findings provide evidence that AFP-enriched DEXs can trigger potent antigen-specific antitumor immune responses and reshape the tumor microenvironment in HCC mice and thus provide a cell-free vaccine option for HCC immunotherapy. Lay summary: Dendritic cell (DC)-derived exosomes (DEXs) form a new class of vaccines for cancer immunotherapy. However, their potency in hepatocellular carcinoma (HCC) remains unknown. Here, we investigated exosomes from HCC antigen-expressing DCs in three different HCC mouse models and proved their feasibility and capability of treating HCC, and thus provide a cell-free vaccine for HCC immunotherapy. 10.1016/j.jhep.2017.05.019

Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Roucourt Bart,Meeussen Sofie,Bao Jie,Zimmermann Pascale,David Guido Cell research Exosomes are secreted vesicles of endosomal origin involved in signaling processes. We recently showed that the syndecan heparan sulfate proteoglycans control the biogenesis of exosomes through their interaction with syntenin-1 and the endosomal-sorting complex required for transport accessory component ALIX. Here we investigated the role of heparanase, the only mammalian enzyme able to cleave heparan sulfate internally, in the syndecan-syntenin-ALIX exosome biogenesis pathway. We show that heparanase stimulates the exosomal secretion of syntenin-1, syndecan and certain other exosomal cargo, such as CD63, in a concentration-dependent manner. In contrast, exosomal CD9, CD81 and flotillin-1 are not affected. Conversely, reduction of endogenous heparanase reduces the secretion of syntenin-1-containing exosomes. The ability of heparanase to stimulate exosome production depends on syntenin-1 and ALIX. Syndecans, but not glypicans, support exosome biogenesis in heparanase-exposed cells. Finally, heparanase stimulates intraluminal budding of syndecan and syntenin-1 in endosomes, depending on the syntenin-ALIX interaction. Taken together, our findings identify heparanase as a modulator of the syndecan-syntenin-ALIX pathway, fostering endosomal membrane budding and the biogenesis of exosomes by trimming the heparan sulfate chains on syndecans. In addition, our data suggest that this mechanism controls the selection of specific cargo to exosomes. 10.1038/cr.2015.29