Tumor-Derived Exosomes Elicit Tumor Suppression in Murine Hepatocellular Carcinoma Models and Humans In Vitro
Tumor-Derived Exosomes Elicit Tumor Suppression in Murine Hepatocellular Carcinoma Models and Humans In Vitro
复制标题
肿瘤源性外泌体在小鼠肝细胞癌模型和人类体外引起肿瘤抑制
DOI：
10.1002/hep.28549
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发表时间：
2016-08-01
期刊：
影响因子：
13.5
通讯作者：
Yin, HaiFang
中科院分区：
文献类型：
--
作者：
Rao, Quan;Zuo, Bingfeng;Yin, HaiFang
肝细胞癌（HCC）由于发病率和死亡率高，治疗效果差，仍然是一个全球性的挑战。免疫治疗，基于引入树突状细胞（DC）激活的肿瘤细胞裂解物作为抗原离体，显示有限的反应率在肝癌患者。在这里，我们证明了肿瘤细胞来源的外泌体（TEX），展示了一系列HCC抗原，可以在体外和体内引起比细胞裂解物更强的免疫应答。在用TEX脉冲的DC处理的异位和原位HCC小鼠中实现了显著的肿瘤生长抑制。重要的是，在经TEX脉冲的DC治疗的原位HCC小鼠中，肿瘤免疫微环境显著改善，表现为肿瘤部位的T淋巴细胞数量增加、干扰素水平升高以及白细胞介素-10和肿瘤生长因子水平降低。正如预期的那样，T细胞在TEX脉冲的DC介导的免疫应答中发挥了重要作用。值得注意的是，来自HCC细胞的外泌体不仅促进HCC特异性细胞溶解，而且还提供针对胰腺癌细胞的交叉保护作用。此外，在不同的人HCC细胞中观察到由人HepG 2细胞来源的外泌体脉冲的DC引起的HCC特异性细胞溶解，而与人白细胞抗原类型无关。结论：HCC TEX可以有效地携带HCC抗原，引发强烈的DC介导的免疫应答，并改善HCC肿瘤微环境。
Hepatocellular carcinoma (HCC) remains a global challenge due to high morbidity and mortality rates and poor response to treatment. Immunotherapy, based on introduction of dendritic cells (DCs) activated by tumor cell lysates as antigens ex vivo, shows limited response rates in HCC patients. Here, we demonstrate that tumor cell-derived exosomes (TEXs), displaying an array of HCC antigens, can elicit a stronger immune response than cell lysates in vitro and in vivo. Significant tumor growth inhibition was achieved in ectopic and orthotopic HCC mice treated with TEX-pulsed DCs. Importantly, the tumor immune microenvironment was significantly improved in orthotopic HCC mice treated by TEX-pulsed DCs, demonstrated by increased numbers of T lymphocytes, elevated levels of interferon-, and decreased levels of interleukin-10 and tumor growth factor- in tumor sites. As expected, T cells played an essential role in the TEX-pulsed DC-mediated immune response. Notably, exosomes from HCC cells not only promoted HCC-specific cytolysis but also provided cross-protective effects against pancreatic cancer cells. Moreover, HCC-specific cytolysis, elicited by DCs pulsed with human HepG2 cell-derived exosomes, was observed across different human HCC cells irrespective of human leukocyte antigen types. Conclusion: HCC TEXs can potently carry HCC antigens, trigger a strong DC-mediated immune response, and improve the HCC tumor microenvironment.