树突状细胞衍生的外泌体在同源性肝细胞肝癌小鼠模型中引发肿瘤消退。

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

机构信息

Department of Cell Biology and Research Centre of Basic Medical Science, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.

出版信息

J Hepatol. 2017 Oct;67(4):739-748. doi: 10.1016/j.jhep.2017.05.019. Epub 2017 May 24.

DOI:10.1016/j.jhep.2017.05.019

PMID:28549917

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) 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.

摘要

背景与目的

树突状细胞（DC）衍生的外泌体（DEX）形成了癌症免疫治疗的一类新疫苗。然而，它们在肝细胞癌（HCC）中的效力仍有待研究，HCC 是一种危及生命的恶性肿瘤，临床上治疗选择有限，对免疫治疗反应不佳。

方法

在三种不同的 HCC 小鼠模型系统中研究了表达甲胎蛋白（AFP）的 DC 衍生的外泌体（DEX）。监测肿瘤生长和微环境。

结果

DEX 引发了强烈的抗原特异性免疫反应，导致荷瘤小鼠的肿瘤生长明显减缓，存活率延长，这些荷瘤小鼠患有异位、原位和致癌物诱导的 HCC 肿瘤，表现出抗原和病理学异质性。DEX 治疗 HCC 小鼠的肿瘤微环境得到改善，表现为肿瘤部位表达γ干扰素（IFN-γ）的 CD8 T 淋巴细胞明显增多，IFN-γ和白细胞介素-2水平升高，CD25Foxp3 调节性 T（Treg）细胞减少，白细胞介素-10 和转化生长因子-β水平降低。在无胸腺裸鼠和 CD8 T 细胞耗竭鼠中缺乏疗效表明 T 细胞有助于 DEX 介导的抗肿瘤功能。在不同时间点对 DEX 治疗的原位 HCC 小鼠的抗肿瘤疗效和免疫微环境进行动态检查表明，肿瘤抑制与免疫微环境之间存在正相关。