Targeting Tumor Antigens to Secreted Membrane Vesicles In vivo Induces Efficient Antitumor Immune Responses

ZEELEMBERG, IS; OSTROWSKI, M; KRUMEICH, S; BOBRIE, A; JANCIC, C; BOISSONNAS, A; DELCAYRE, A; LE PECQ, J.B; COMBADIERE, B; AMIGORENA, S; THERY, C

CANCER RESEARCH

Año: 2008 vol. 68 p. 1228 - 1235

0008-5472

Expression of non-self antigens by tumors can induceactivation of T cells in vivo, although this activation can leadto either immunity or tolerance. CD8+ T-cell activation can bedirect (if the tumor expresses MHC class I molecules) orindirect (after the capture and cross-presentation of tumorantigens by dendritic cells). The modes of tumor antigencapture by dendritic cells in vivo remain unclear. Here weexamine the immunogenicity of the same model antigensecreted by live tumors either in association with membranevesicles (exosomes) or as a soluble protein. We have artificiallyaddressed the antigen to secreted vesicles by coupling it to thefactor VIII–like C1C2 domain of milk fat globule epidermalgrowth factor-factor VIII (MFG-E8)/lactadherin. We show thatmurine fibrosarcoma tumor cells that secrete vesicle-boundantigen grow slower than tumors that secrete soluble antigenin immunocompetent, but not in immunodeficient, host mice.This growth difference is due to the induction of a morepotent antigen-specific antitumor immune response in vivo bythe vesicle-bound than by the soluble antigen. Finally, in vivosecretion of the vesicle-bound antigen either by tumors or byvaccination with naked DNA protects against soluble antigensecretingtumors. We conclude that the mode of secretion candetermine the immunogenicity of tumor antigens and thatmanipulation of the mode of antigen secretion may be used tooptimize antitumor vaccination protocols.