title: Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity.
abstract: Immunization of mice with plasmids encoding xenogeneic orthologues of tumor differentiation antigens can break immune ignorance and tolerance to self and induce protective tumor immunity. We sought to improve on this strategy by combining xenogeneic DNA vaccination with an agonist anti-glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) monoclonal antibody (mAb), DTA-1, which has been shown previously both to costimulate activated effector CD4(+) and CD8(+) T cells and to inhibit the suppressive activity of CD4(+)CD25(+) regulatory T cells. We found that ligation of GITR with DTA-1 just before the second, but not the first, of 3 weekly DNA immunizations enhanced primary CD8(+) T-cell responses against the melanoma differentiation antigens gp100 and tyrosinase-related protein 2/dopachrome tautomerase and increased protection from a lethal challenge with B16 melanoma. This improved tumor immunity was associated with a modest increase in focal autoimmunity, manifested as autoimmune hypopigmentation. DTA-1 administration on this schedule also led to prolonged persistence of the antigen-specific CD8(+) T cells as well as to an enhanced recall CD8(+) T-cell response to a booster vaccination given 4 weeks after the primary immunization series. Giving the anti-GITR mAb both during primary immunization and at the time of booster vaccination increased the recall response even further. Finally, this effect on vaccine-induced CD8(+) T-cell responses was partially independent of CD4(+) T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8(+) cells themselves.
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. cohena@mskcc.org
authors.forename: Adam D
authors.initials: AD
authors.lastname: Cohen
authors.forename: Adi
authors.initials: A
authors.lastname: Diab
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Perales
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rizzuto
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Deonka
authors.initials: D
authors.lastname: Huggins
authors.forename: Cailian
authors.initials: C
authors.lastname: Liu
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007114:Immunization / Q000379:methods; D007156:Immunologic Memory; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology* / Q000494:pharmacology; D058951:gp100 Melanoma Antigen
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C548642:Pmel protein, mouse; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C113139:Trp2 protein, vertebrate; D019444:Vaccines, DNA; D058951:gp100 Melanoma Antigen