Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

Abstract

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.

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

“…For example, EVs from activated CD8+ T-cells can increase tumor immunogenicity by activating ERK and NFκB signaling through TNF-related signaling leading ultimately to the upregulation of MMP-9. This chain of events increases the metastatic potential in melanoma and lung cancer 11 . In another chain of events pancreatic ductal adenocarcinomas cell-derived EVs can lead to pre-metastatic niche formation in sequential steps of induction of TGFβ signaling in Kupffer cells leading to extracellular matrix modification and subsequently an influx of bone marrow-derived macrophages to the liver, providing a favorable niche for liver metastasis 19 .…”

Effects of FasL Expression in Oral Squamous Cell Cancer

“…Accordingly,they become more sensitive to apoptosis when they interact with cells that express the FasL on their surface (Nagata et al, 1995;Ehrenschwender et al, 2009). Evidence for this mechanism of tumor immune privilege has been provided for several cancers (Zhou et al, 2006;Wu et al, 2010;Gomes et al, 2011;Cai et al, 2012;Tian et al, 2012;Wang et al, 2012) that have been shown to express FasL, including skin, lung, breast, and cervical cancers, gastric cancer. To date, the molecular events underlying the role of Fas/FasL in the progression to oral carcinoma are poorly understood (Chen et al, 1999).…”

The Multiple Roles of Exosomes in Metastasis

“…Exosomes derived from activated T-cells were shown to promote B16 melanoma and Lewis lung cell metastasis to the lung (86). Activation of the Fas/FasL pathway in tumor cells, increase in FLICE inhibitory proteins, activation of ERK-and NFĸB signaling and the resulting increase in MMP9 activity were shown to be responsible for promotion of metastasis (124). However, most investigations on immune-mechanisms based promotion of metastasis were performed with TC-derived exosomes.…”