Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models

Abstract

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_AFP) were investigated in three different HCC mouse models systemically. Tumor growth and microenvironment were monitored.

Results: DEX_AFP 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_AFP-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 CD25⁺Foxp3⁺ 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_AFP-mediated antitumor function. Dynamic examination of the antitumor efficacy and the immune microenvironment in DEX_AFP-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.

Keywords: Alpha-fetoprotein; Carcinogen; Dendritic cells; Exosome; Hepatocellular carcinoma; Immunotherapy; Interferon; Interleukin.