title: Tumor-produced secreted form of binding of immunoglobulin protein elicits antigen-specific tumor immunity.
abstract: Binding of immunoglobulin protein (BiP) is a major molecular chaperone localized in endoplasmic reticulum (ER). It has been demonstrated to interact with nascent Ig. However, contrary to other ER-resident heat shock proteins such as gp96, calreticulin, and ORP150, it is not clear whether tumor-derived BiP plays a role in inducing antitumor immunity. In this study, we show that the tumor-derived secreted form of BiP is capable of inducing antitumor CD8(+) T cell responses. We constructed an ER-retention signal KDEL-deleted mutant of BiP cDNA and transfected it to tumor cells, which resulted in continuous secretion of tumor-derived BiP into the extracellular milieu. We show that this secreted BiP is taken up by bone marrow-derived dendritic cells, and thereafter BiP-associated Ag peptide is cross-presented in association with MHC class I molecules, resulting in elicitation of an Ag-specific CD8(+) T cell response and antitumor effect. This strategy to boost antitumor immune responses shows that a tumor could be its own cellular vaccine via gene modification of the secretion of the tumor Ag-BiP complex.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556, Japan. ytamura@sapmed.ac.jp
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Goro
authors.initials: G
authors.lastname: Kutomi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Kamiguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology; D000091342:Endoplasmic Reticulum Chaperone BiP; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D013945:Thymoma / Q000276:immunology* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D000939:Epitopes; D006360:Heat-Shock Proteins