Abstract
Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic cells). The modes of tumor antigen capture by dendritic cells in vivo remain unclear. Here we examine the immunogenicity of the same model antigen secreted by live tumors either in association with membrane vesicles (exosomes) or as a soluble protein. We have artificially addressed the antigen to secreted vesicles by coupling it to the factor VIII-like C1C2 domain of milk fat globule epidermal growth factor-factor VIII (MFG-E8)/lactadherin. We show that murine fibrosarcoma tumor cells that secrete vesicle-bound antigen grow slower than tumors that secrete soluble antigen in immunocompetent, but not in immunodeficient, host mice. This growth difference is due to the induction of a more potent antigen-specific antitumor immune response in vivo by the vesicle-bound than by the soluble antigen. Finally, in vivo secretion of the vesicle-bound antigen either by tumors or by vaccination with naked DNA protects against soluble antigen-secreting tumors. We conclude that the mode of secretion can determine the immunogenicity of tumor antigens and that manipulation of the mode of antigen secretion may be used to optimize antitumor vaccination protocols.
Highlights
Activation of tumor-specific T cells is observed in mice bearing growing tumors, this T-cell response does not necessarily lead to tumor eradication and can even result in tolerance [1, 2]
Tumors and cross-present them to CD8+ T cells using various sources of antigenic material: dead tumor cells [3], heat shock protein-peptide complexes purified from tumor lysates [4], plasma membrane fragments that dendritic cells capture by ‘‘nibbling’’ from live tumors [5], soluble proteins [6], or vesicles secreted by live tumor cells, called exosomes [7]
We show here that in vivo secretion by live cells of an antigen fused to the C1C2 domain of MFG-E8/lactadherin promotes antigen-specific immune responses, resulting in delay of the growth of antigen-bearing tumors
Summary
Activation of tumor-specific T cells is observed in mice bearing growing tumors, this T-cell response does not necessarily lead to tumor eradication and can even result in tolerance [1, 2]. Because only professional antigen-presenting cells, especially dendritic cells, are able to prime immune responses, activation of T cells specific for tumor antigens must involve an indirect pathway of antigen presentation: antigen-presenting cells acquire antigens from tumors and present them as MHC class I-peptide and MHC class II-peptide complexes to CD8+ and CD4+ T cells. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-07-3163 tumors and cross-present them to CD8+ T cells using various sources of antigenic material: dead (apoptotic or necrotic) tumor cells [3], heat shock protein-peptide complexes purified from tumor lysates [4], plasma membrane fragments that dendritic cells capture by ‘‘nibbling’’ from live tumors [5], soluble proteins [6], or vesicles secreted by live tumor cells, called exosomes [7] I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-3163 tumors and cross-present them to CD8+ T cells using various sources of antigenic material: dead (apoptotic or necrotic) tumor cells [3], heat shock protein-peptide complexes purified from tumor lysates [4], plasma membrane fragments that dendritic cells capture by ‘‘nibbling’’ from live tumors [5], soluble proteins [6], or vesicles secreted by live tumor cells, called exosomes [7]
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