title: Antigen localization controls T cell-mediated tumor immunity.
abstract: Effective antitumor immunotherapy requires the identification of suitable target Ags. Interestingly, many of the tumor Ags used in clinical trials are present in preparations of secreted tumor vesicles (exosomes). In this study, we compared T cell responses elicited by murine MCA101 fibrosarcoma tumors expressing a model Ag at different localizations within the tumor cell in association with secreted vesicles (exosomes), as a nonsecreted cell-associated protein, or as secreted soluble protein. Remarkably, we demonstrated that only the tumor-secreting vesicle-bound Ag elicited a strong Ag-specific CD8(+) T cell response, CD4(+) T cell help, Ag-specific Abs, and a decrease in the percentage of immunosuppressive regulatory T cells in the tumor. Moreover, in a therapeutic tumor model of cryoablation, only in tumors secreting vesicle-bound Ag could Ag-specific CD8(+) T cells still be detected up to 16 d after therapy. We concluded that the localization of an Ag within the tumor codetermines whether a robust immunostimulatory response is elicited. In vivo, vesicle-bound Ag clearly skews toward a more immunogenic phenotype, whereas soluble or cell-associated Ag expression cannot prevent or even delay outgrowth and results in tumor tolerance. This may explain why particular immunotherapies based on these vesicle-bound tumor Ags are potentially successful. Therefore, we conclude that this study may have significant implications in the discovery of new tumor Ags suitable for immunotherapy and that their location should be taken into account to ensure a strong antitumor immune response.
authors.affiliation: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, The Netherlands. I.Zeelenberg@ncmls.ru.nl
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Zeelenberg
authors.forename: Wendy W C
authors.initials: WW
authors.lastname: van Maren
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boissonnas
authors.forename: Maaike A
authors.initials: MA
authors.lastname: Van Hout-Kuijer
authors.forename: Martijn H M G M
authors.initials: MH
authors.lastname: Den Brok
authors.forename: Jori A L
authors.initials: JA
authors.lastname: Wagenaars
authors.forename: Alie
authors.initials: A
authors.lastname: van der Schaaf
authors.forename: Eric J R
authors.initials: EJ
authors.lastname: Jansen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.forename: Clotilde
authors.initials: C
authors.lastname: Théry
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D011961:Receptors, Fc; D010047:Ovalbumin