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Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.

ABSTRACT: The antitumor immune response is a critical defense system that eliminates malignant cells. The failure of the system results in immune escape and proceeds to tumor growth. We have previously showed that estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a relevant cancer biomarker and facilities immune escape of cancers from the immune surveillance. EBAG9 in cancer cells suppresses T-cell infiltration into tumor in vivo, whereas that in host immune cells functions as a limiter for T-cell cytotoxicity. Considering that EBAG9 plays immune suppressive roles in both tumor and microenvironment, we here questioned whether EBAG9 is a transferable protein from cancer to surrounding T cells and affects antitumor immune response. In this study, we showed that spontaneous development of prostate cancer was repressed in a model of Ebag9 knockout mice crossed with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. We identified TM9SF1 as a collaborative EBAG9 interactor, which regulates epithelial-mesenchymal transition (EMT) in cancer cells. Notably, extracellular vesicles (EVs) from EBAG9-overexpressing prostate cancer cells have a potential to facilitate immune escape of tumors by inhibiting T-cell cytotoxicity and modulating immune-related gene expression in T cells. Furthermore, we showed that a neutralizing antibody for EBAG9 could rescue the EV-mediated immune suppression by recovering T-cell cytotoxicity. In addition to its autocrine functions in cancer cells, EBAG9 could behave as a new class of immune checkpoint that suppresses tumor immunity in a secretory manner. We propose that EBAG9-targeting cancer treatment could be alternative therapeutic options for advanced diseases, particularly for those with EBAG9 overexpression.

SUBMITTER: Miyazaki T

PROVIDER: S-EPMC5833691 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.

Miyazaki Toshiaki T Ikeda Kazuhiro K Sato Wataru W Horie-Inoue Kuniko K Inoue Satoshi S

Oncogenesis 20180124 1

The antitumor immune response is a critical defense system that eliminates malignant cells. The failure of the system results in immune escape and proceeds to tumor growth. We have previously showed that estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a relevant cancer biomarker and facilities immune escape of cancers from the immune surveillance. EBAG9 in cancer cells suppresses T-cell infiltration into tumor in vivo, whereas that in host immune cells functions as a limiter f ...[more]

PMID: 29362448

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Project description:Background: Glioblastoma (GBM) is one of the most aggressive types of brain cancer. GBM progression is closely associated with microglia activation; therefore, understanding the regulation of the crosstalk between human GBM and microglia may help develop effective therapeutic strategies. Elucidation of efficient delivery of microRNA (miRNA) via extracellular vesicles (EVs) and their intracellular communications is required for therapeutic applications in GBM treatment. Methods: We used human GBM cells (U373MG) and human microglia. MiRNA-124 was loaded into HEK293T-derived EVs (miR-124 EVs). Various anti-tumor effects (proliferation, metastasis, chemosensitivity, M1/M2 microglial polarization, and cytokine profile) were investigated in U373MG and microglia. Anti-tumor effect of miR-124 EVs was also investigated in five different patient-derived GBM cell lines (SNU-201, SNU-466, SNU-489, SNU-626, and SNU-1105). A three-dimensional (3D) microfluidic device was used to investigate the interactive microenvironment of the tumor and microglia. Results: MiR-124 EVs showed highly efficient anti-tumor effects both in GBM cells and microglia. The mRNA expression levels of tumor progression and M2 microglial polarization markers were decreased in response to miR-124 EVs. The events were closely related to signal transducer and activator of transcription (STAT) 3 signaling in both GBM and microglia. In 3D microfluidic experiments, both U373MG and microglia migrated to a lesser extent and showed less-elongated morphology in the presence of miR-124 EVs compared to the control. Analyses of changes in cytokine levels in the microfluidic GBM-microglia environment showed that the treatment with miR-124 EVs led to tumor suppression and anti-cancer immunity, thereby recruiting natural killer (NK) cells into the tumor. Conclusions: In this study, we demonstrated that EV-mediated miR-124 delivery exerted synergistic anti-tumor effects by suppressing the growth of human GBM cells and inhibiting M2 microglial polarization. These findings provide new insights toward a better understanding of the GBM microenvironment and provide substantial evidence for the development of potential therapeutic strategies using miRNA-loaded EVs.

Dataset Information

Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.

Publications

Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression.

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