Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

Abstract

Dendritic and lymphoid 'exosomes' regulate immune activation. Tumours release membranous material mimicking these 'exosomes,' resulting in deletion of reactive lymphocytes. Tumour-derived 'exosomes' have recently been explored as vaccines, without analysis of their immunologic consequences. This investigation examines the composition of tumour-derived 'exosomes' and their effects on T lymphocytes. Membranous materials were isolated from ascites of ovarian cancer patients (n ¼ 6) and Western immunoblotting was performed for markers associated with 'exosomes.' Using cultured T cells, 'exosomes' were evaluated for suppression of CD3-z and JAK 3 expressions and induction of apoptosis, measured by DNA fragmentation. 'Exosome' components mediating suppression of CD3-z were isolated by continuous eluting electrophoresis and examined by Western immunoblotting. 'Exosomes' were shown to be identical with previously characterised shed membrane vesicles by protein staining and TSG101 expression. 'Exosomes' expressed class I MHC, placental alkaline phosphatase, B23/nucleophosmin, and FasL. 'Exosomes' suppressed expression of T-cell activation signalling components, CD3-z and JAK 3 and induced apoptosis. CD3-z suppression was mediated by two components: 26 and 42 kDa. Only the 42 kDa component reacted with anti-FasL antibody. These results indicate that, while 'exosomes' express tumour antigens, leading to their proposed utility as tumour vaccines, they also can suppress T-cell signalling molecules and induce apoptosis.

Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis

“…This is exemplified by the recruitment of the majority of melanoma cells to the left PO sentinel node where they are buffered by an even greater number of melanoma exosomes. Given our data and the numerous reports of tumor exosome-mediated immune suppression (11)(12)(13), it seems logical that tumor exosomes would have a role in conditioning sentinel lymph nodes for the controlled spread of metastasis whereby routes of communication between primary and metastatic tumors can be efficiently maintained.…”

“…A, melanoma exosomes home to sentinel lymph nodes. B, within sentinel nodes, melanoma exosomes prepare a premetastic niche by inducing expression of factors responsible for cell recruitment, matrix remodeling, and angiogenesis (15) and likely mediate immunosuppression (12,45). C, metastatic melanoma or stem cells travel to the prepared niche where they encounter a microenvironment conducive to tumor cell adherence and growth.…”

“…The nanoscale size of exosomes facilitates their penetration and interaction with local tumor cells as well as with cell types that are distant to an advancing tumor cell front. This may result in tumor immune evasion by direct suppression of T cell activation and induction of apoptosis (12), suppression of the antitumor activity of natural killer cells (13) and other mechanisms (14).…”

Tumour-released exosomes and their implications in cancer immunity

“…in head and neck cancer or ovarian carcinoma), could be reproduced with microvesicles isolated from plasma of cancer patients and may help to explain the high frequency of apoptotic or CD3-zeta neg lymphocytes that are often found in the peripheral circulation of these patients. 46,47 Other immune effectors, such as for instance natural killer cells, are not spared from these negative influences as they lose their cytolytic potential, through the downmodulation of perforin expression, upon encounter with tumour-secreted microvesicles. 48 These data, together with those collected by other groups, 41,49 suggest that exosomes might also act as a vehicle for suppressive signals and have negative effects on antitumour immune responses.…”

The exosomes in tumor immunity

“…[48][49][50] Fas ligand (FasL)-positive membranous exosomes isolated from sera of oral cancer patients could induce apoptosis of activated T lymphocytes. 51 TEXs could also mediate Fas/FasL-associated apoptosis of CD8 C T cells and downregulate expression of CD3z and Janus kinase 3 (JAK3) in activated T cells.…”