title: Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity.
abstract: Glucocorticoid-induced TNF receptor family related protein (GITR) is present on many different cell types. Previous studies have shown that in vivo administration of an anti-GITR agonist mAb (DTA-1) inhibits regulatory T cells (Treg)-dependent suppression and enhances T cell responses. In this study, we show that administration of DTA-1 induces >85% tumor rejection in mice challenged with B16 melanoma. Rejection requires CD4+, CD8+, and NK1.1+ cells and is dependent on IFN-gamma and Fas ligand and independent of perforin. Depletion of Treg via anti-CD25 treatment does not induce B16 rejection, whereas 100% of the mice depleted of CD25+ cells and treated with DTA-1 reject tumors, indicating a predominant role of GITR on effector T cell costimulation rather than on Treg modulation. T cells isolated from DTA-1-treated mice challenged with B16 are specific against B16 and several melanoma differentiation Ags. These mice develop memory against B16, and a small proportion of them develop mild hypopigmentation. Consistent with previous studies showing that GITR stimulation increases Treg proliferation in vitro, we found in our model that GITR stimulation expanded the absolute number of FoxP3+ cells in vivo. Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity.
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. tramirez@mail.rockefeller.edu
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramirez-Montagut
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
authors.forename: Daniel
authors.initials: D
authors.lastname: Hirschhorn-Cymerman
authors.forename: Theis H
authors.initials: TH
authors.lastname: Terwey
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kochman
authors.forename: Sydney
authors.initials: S
authors.lastname: Lu
authors.forename: Randy C
authors.initials: RC
authors.lastname: Miles
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm; D045744:Cell Line, Tumor; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006084:Graft Rejection; D007108:Immune Tolerance / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology*; D009368:Neoplasm Transplantation; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D015533:Transcriptional Activation
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D053450:Glucocorticoid-Induced TNFR-Related Protein; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse