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Toll‐like Receptor‐4 Activation Improves the Immunosuppressive Properties of Cancer Cells‐Derived Exosomes
Author(s) -
Domenis Rossana,
Marinò Daniele,
Cifù Adriana,
Fabris Martina,
Niazi Kayvan R.,
SoonShiong Patrick,
Curcio Francesco
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.677.22
Subject(s) - microvesicles , cancer research , exosome , flow cytometry , cancer cell , metastasis , immune system , biology , chemistry , cancer , immunology , microrna , biochemistry , genetics , gene
Tumor cells actively produce and release exosomes to promote tumor growth and progression. Upon the contact with target cells, exosomes alter phenotypic and functional features of recipients, reprogramming them into active contributors to metastasis and immunosuppression. Overexpression of Toll‐like receptor‐4 has been implicated in the development of several types of cancer, since its activation increase their tumorigenic potential of cancer cells. The purpose of this study is to investigate the immunosuppressive properties of cancer cell‐derived exosomes released upon TLR4 activation by LPS. Cancer cell lines (primary colon SW480, metastatic colon SW620, metastatic breast MDA‐MG‐231 and glioma U87) were treated with LPS (1μg/ml) for 24h and then cultured in exosome‐free medium for 48h. Exosomes were isolated from cells supernatants by polymer precipitation method (Exoquick), quantified by determining the activity of Acetyl‐CoA Esterase (Exocet test) and validated by exosome‐specific tetraspanins expression by western blot and flow cytometry analysis. The expression of immunosuppressive factors on exosomes surface was evaluated by flow cytometry and Multiplex ELISA. Exosomes immuneregulatory properties were assessed by in vitro functional assays on immune cell subpopulations isolated from healthy donor's blood. We demonstrated that the treatment with LPS enhances the immunosuppressive potential of cancer cells‐derived exosomes, although differences were observed depending on the origin of the tumor. The expression of TGFβ and MICA/B was increased on surface of exosomes released from LPS‐stimulated cells. Moreover, exosomes became able to inhibit the proliferation of activated CD3+ cells, increase T cells apoptosis and promote the conversion of CD4+ in regulatory T cells. Our data suggest that the activation of TLR4 contributes to tumor progression by promoting the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .