Tumor cells release membranous structures, defined as microvesicles or exosomes, consisting of an array of macromolecules derived from the originating cells, including proteins, lipids, and RNA. The expression of antigenic molecules recognizable by T cells originally suggested a role for these vesicles as a cell-free antigen source for anti-cancer vaccines; however, evidence demonstrates that tumor exosomes can exert a broad array of detrimental effects on the immune system - ranging from apoptosis of activated cytotoxic T cells to impairment of monocyte differentiation into dendritic cells, to induction of myeloid-suppressive cells. Immunosuppressive exosomes of tumor origin can be found in neoplastic lesions and biologic fluids from cancer patients, implying a potential role of these pathways in in vivo tumor progression and systemic paraneoplastic syndromes. Through the expression of molecules involved in angiogenesis promotion, stromal remodeling, signaling pathway activation through growth factor/receptor transfer, chemoresistance, and intercellular genetic exchange, tumor exosomes could represent a central mediator of the tumor microenvironment. Their release by tumor cells may represent the future for targeting therapeutic interventions and for development of multiplexed diagnostic biomarkers.
The tumour microenvironment is characterized by pro-inflammatory profiles, including interleukin-1 (IL-1β). This profile is generated by infiltrating macrophages following interactions with tumours or their components. The objectives of this study were to identify whether tumour exosomes could induce macrophage IL-1β production and the mechanism involved. Exosomes were isolated from ovarian cancer patients and ovarian tumour cells by chromatography and ultracentrifugation. Specific exosomal proteins were defined by mass spectrometry (MS) and confirmed by Western immunoblotting. Using macrophage-like THP-1 cells, induction of IL-1β release was investigated by ELISA. RGD peptides were used to block fibronectin binding by THP-1 51 integrin. Exosomes isolated from ovarian cancer patients and from ovarian cancer cells were demonstrated, by MS and immunoblotting, to express fibronectin. Incubation of THP-1 cells with these exosomes induced pro-inflammatory cytokines, in particular IL-1β. Blocking of THP-1 binding of exosomal fibronectin with RGD peptides abrogated exosome-mediated IL-1β production and downstream phosphorylation of Akt and c-Jun. Although cancer patients generally exhibit increased levels of IL-1β, the underlying mechanism is unclear. Here, tumourderived exosomes are demonstrated to induce proinflammatory cytokine in macrophages including IL-1, whose induction is mediated by fibronectin.
Altered tumour antigens can initiate cellular and humoral immune responses; however, they often fail to eliminate tumours. In humans, the presence of cancer is generally associated with the suppression of T cell activation and effector responses, characterized as a Th1 to Th2 biased response. This Th2 response leads to the production of tumour-reactive antibodies. Further, neoplastic lesions and biological fluids of cancer patients contain an abundance of tumour-derived exosomes (TDE) expressing tumour antigens. Expression of tumour antigens on TDE may represent an antibody target and serve to block antibody binding to the tumour, implicating a role for these nanovesicles in tumour survival. In this study, ovarian tumour cell proteins were separated by two-dimensional electrophoresis (2-DE) and patient-derived antibodies were used to analyse immunoreactivity. Common immunoreactive proteins among ovarian cancer patients were identified by mass spectrometry and six proteins were selected based on recognition and correlation with cancer pathogenesis. The identity of these proteins were confirmed by immunoreactivity of patient-derived antibodies with recombinant proteins and their presence on in vivo and in vitro-derived ovarian tumour exosomes was defined. Analysis of the TDE demonstrated bound tumour-reactive immunoglobulins, exhibiting immunoreactivity with specific antigens, suggesting that patient-derived antibodies recognize tumour antigens on circulating exosomes.
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