Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway
Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway
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激活的 T 细胞外泌体通过 Fas 信号通路促进肿瘤侵袭
DOI：
10.4049/jimmunol.1103466
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发表时间：
2012-06-15
影响因子：
4.4
通讯作者：
Wang, Jianli
中科院分区：
文献类型：
--
作者：
Cai, Zhijian;Yang, Fei;Wang, Jianli
活化的T细胞在外泌体中释放生物活性Fas配体（FasL），随后诱导T细胞自我凋亡。然而，它们对肿瘤细胞凋亡的潜在影响尚不清楚。本研究从OT-I小鼠活化的CD8+ T细胞中纯化表达FasL的外泌体，发现活化的T细胞外泌体对肿瘤细胞的凋亡和增殖影响不大，但在体外通过Fas/FasL途径促进B16和3LL癌细胞的侵袭。激活的T细胞外泌体增加了细胞FLICE抑制蛋白的数量，随后激活了ERK和NF-κB通路，从而增加了B16小鼠黑色素瘤细胞中MMP9的表达。在体内肿瘤侵袭模型中，我们观察到活化的T细胞外泌体促进了B16肿瘤细胞向肺的迁移。有趣的是，FasL mAb预处理显著降低了B16肿瘤细胞向肺的迁移。此外，来自肿瘤小鼠而非正常小鼠的CD8和FasL双阳性外泌体也增加了MMP9的表达，并促进了B16小鼠黑色素瘤和3LL肺癌细胞的侵袭能力。综上所述，我们的研究结果表明，激活的T细胞外泌体通过Fas信号通路增加MMP9的表达，促进黑色素瘤和肺癌细胞转移，揭示了肿瘤免疫逃逸的新机制。
Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8+ T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape.