title: Fusion protein of mutant B7-DC and Fc enhances the antitumor immune effect of GM-CSF-secreting whole-cell vaccine.
abstract: B7-DC [also known as programmed death ligand 2 (PD-L2)] is a costimulatory molecule expressed predominantly on dendritic cells (DCs) and macrophages. In addition to its coinhibitory receptor, programmed death receptor 1 (PD-1), evidence suggests that B7-DC interacts with an unidentified costimulatory receptor on T cells. B7-DC mutants with selective binding capacity for the costimulatory receptor may be effective in stimulating antitumor immune responses, while avoiding the inhibitory effects of PD-1. In this study, we concomitantly administered a GM-CSF-secreting whole-cell vaccine together with a fusion protein of mutant B7-DC and Fc portion (mB7-DC-Fc), which binds selectively to the costimulatory receptor. This lead to an increased number of tumor antigen-specific cytotoxic T lymphocytes both in the spleen and at the tumor site and complete elimination of established tumors in vivo. In addition, mB7-DC-Fc increased IFN-γ and IL-2 production and decreased IL-4 and IL-10 production in vitro, indicating that mB7-DC-Fc tips the Th1/Th2 balance toward Th1 dominance, which is more favorable for antitumor immunity. Furthermore, mB7-DC-Fc decreased the PD-1(+) proportion of CD8(+) T cells in vitro and tumor-infiltrating CD8(+) T cells in vivo, suggesting that mB7-DC-Fc may maintain tumor-infiltrating CD8(+) T cells in a nonexhausted state. In conclusion, mB7-DC-Fc administration during the T-cell priming phase enhances antitumor effects of vaccine by generating more tumor antigen-specific cytotoxic T lymphocytes and leading to their accumulation at the tumor site. We suggest that this combination approach may be a promising strategy for antitumor immunotherapy.
authors.affiliation: *Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan †The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Kojima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murata
authors.forename: Eiji
authors.initials: E
authors.lastname: Mekata
authors.forename: Katsushi
authors.initials: K
authors.lastname: Takebayashi
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: Tohru
authors.initials: T
authors.lastname: Tani
mesh_terms: D000818:Animals; D016466:CHO Cells; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010455:Peptides / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C556978:Pdcd1lg2 protein, mouse; C524056:Erbb2 protein, mouse