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

Oncogenesis (2018-01-25)
Toshiaki Miyazaki, Kazuhiro Ikeda, Wataru Sato, Kuniko Horie-Inoue, Satoshi Inoue
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.

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Anti-Vimentin antibody produced in rabbit, affinity isolated antibody

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