Abstract
Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs.
Highlights
Tumor cells usually express tumor-specific or tumor-associated antigens which are potentially immunogenic [1], established tumors are able to induce immunosuppression and even tolerance to these antigens
We demonstrate that exosomes derived from tumor cells stably expressing the model antigen OVA, were able to induce suppression of the OVA-specific delayed-type hypersensitivity (DTH) response
The suppression of DTH response was observed only with antigencontaining tumor exosomes and was specific to the immune response induced by that particular antigen
Summary
Tumor cells usually express tumor-specific or tumor-associated antigens which are potentially immunogenic [1], established tumors are able to induce immunosuppression and even tolerance to these antigens. Release of exosomes by tumor cells has been recognized as one of the mechanisms through which tumor cells can suppress the anti-tumor immune responses [5,6]. Tumorderived exosomes usually contain tumor antigens [6,10,11,12,13] and have been used as a novel source of tumor antigens for cell-free cancer vaccines [11,14,15]. Induction of protective anti-tumor responses has been observed when tumorderived exosomes were used to pulse mature DCs or when the exosomes applied were isolated from tumor cells genetically modified to express proinflmmatory cytokines or have elevated levels of stress proteins [11,16,17,18,19]. Targeting antigens to the exosome membrane surface appears to enhance the immunogenicity of tumor-derived exosomes [20,21]
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