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

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 = 6) and Western immunoblotting was performed for markers associated with ' exosomes.' Using cultured T cells, ' exosomes' were evaluated for suppression of CD3-zeta and JAK 3 expressions and induction of apoptosis, measured by DNA fragmentation. ' Exosome' components mediating suppression of CD3-zeta 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-zeta and JAK 3 and induced apoptosis. CD3-zeta 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.