Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions
Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions
复制标题
胃癌细胞来源的外泌体通过调节免疫功能来免疫抑制肿瘤微环境
DOI：
10.1038/s41598-020-71573-y
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发表时间：
2020-09-08
影响因子：
4.6
通讯作者：
Jiang, Jingting
中科院分区：
文献类型：
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作者：
Liu, Juan;Wu, Shaoxian;Jiang, Jingting
胃癌是癌症相关死亡的主要原因之一，其诊断较晚且转移频率高。本研究利用从胃癌细胞系MKN-28、MKN-45和SGC-7901分离的外泌体，研究肿瘤分泌外泌体对肿瘤环境中免疫功能的影响。结果表明，来自所有这些细胞系的外泌体改变了CD8+T细胞的基因表达和细胞因子分泌水平。它们还阻断细胞周期进程，诱导CD8+T细胞凋亡。对三种细胞系的荧光标记外泌体的图像分析显示，这些外泌体主要定位于肺部。我们进一步发现肺外泌体主要被自然杀伤细胞和巨噬细胞吞噬。长期暴露于注射来自MKN-45细胞的外泌体后，小鼠在肺中形成免疫抑制的肿瘤微环境，效应记忆CD4+T和MDSC频率增加，CD8+T细胞和NK频率降低。这种免疫抑制环境促进了胃癌的肺转移。当小鼠注射MFC细胞时，小鼠暴露于从所有三种胃癌细胞系分离的外泌体后，出现肺转移部位。结果表明，来自胃癌细胞（特别是MKN-45和MKN-28）的外泌体改变了CD8+T细胞基因表达和细胞因子分泌模式，为肺转移生态位的形成创造了免疫抑制条件。总的来说，这项研究为胃癌来源的外泌体如何调节免疫反应促进肺肿瘤转移提供了新的见解。
Gastric cancer is one of the leading causes of cancer-related death due to late diagnosis with high metastatic frequency. In this study, the impact of tumor secreted exosomes on immune function in the tumor environment was investigated using exosomes isolated from gastric cancer cell lines MKN-28, MKN-45, and SGC-7901. Results show that exosomes derived from all of these cell lines changed the gene expression and cytokine secretion levels of CD8+T cells. They also block cell cycle progression, induced apoptosis in CD8+T cells. Image analysis of fluorescent labeled exosomes derived from three cell lines injected systemically into C57BL/6 mice revealed these exosomes primarily localize to the lungs. We further showed exosomes were mainly taken up by natural killer cells and macrophages in the lung. After long-term exposure to inject exosomes from MKN-45 cells, mice developed an immunosuppressive tumor microenvironment in the lung with increased frequency of effector memory CD4+T and MDSC, decreased CD8+T cell and NK frequency. This immune suppressive environment promotes gastric cancer lung metastasis. Lung metastasis sites developed after mice were exposed to exosomes isolated from all three gastric cancer cell lines when the mice were injected with MFC cells. Results suggest that exosomes derived from gastric cancer cells (especially MKN-45 and MKN-28) changed CD8+T cell gene expression and cytokine secretion patterns to create an immunosuppressive condition for metastatic niche formation in the lung. Overall, this study provides new insights into how gastric cancer derived exosomes modulate the immune response to promote lung tumor metastasis.