Targeting Tumor Antigens to Secreted Membrane VesiclesIn vivoInduces Efficient Antitumor Immune Responses

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 antigensecreting 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. [Cancer Res 2008;68(4):1228-35]

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

“…One method commonly used to modify the surface proteins of EVs is called the “binding method,” which involves combining the “cargo” protein with a protein localized on the surface of the EVs by gene modification 20, 105, 106, 107. Already used binding segments include the C1C2 domain of milk fat globule‐EGF factor 8 protein,105, 106 the transmembrane domain of platelet‐derived growth factor receptor,107 and the extraexosomal N‐terminal of Lamp2b 20.…”

“…Already used binding segments include the C1C2 domain of milk fat globule‐EGF factor 8 protein,105, 106 the transmembrane domain of platelet‐derived growth factor receptor,107 and the extraexosomal N‐terminal of Lamp2b 20. Another method is called the “membrane‐anchored method” and involves anchoring the “cargo” protein to the membrane by fusing it to oligomeric membrane‐anchored proteins instead of certain EV‐related proteins 108.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…[95][96][97] The protumorigenic vs antitumorigenic roles of TCMVs are governed by the immune status of the patient and the stage of cancer progression. 96 Microvesicles generated from other cells such as platelets, dendritic cells, lymphocytes, monocytes, and stromal fibroblasts in the tumor microenvironment have been observed to modulate progression of the tumor 91,98 (Table 2).…”

Therapeutic biomaterials based on extracellular vesicles: classification of bio‐engineering and mimetic preparation routes

“…Lactadherin C1C2 domain was also used for similar purposes by Zeelemberg et al [65] and Hartman et al [66] to induce expression of chicken egg ovalbumin (OVA) peptide and the human epidermal growth factor receptor 2 antigen (HER2), respectively. Álvarez-Erviti et al [67] described a method of inducing surface expression of the central nervous system-specific rabies viral glycoprotein (RVG) peptide on exosomes isolated from immature dendritic cells derived from mice.…”