Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity Journal Article


Authors: Ramirez-Montagut, T.; Chow, A.; Hirschhorn-Cymerman, D.; Terwey, T. H.; Kochman, A. A.; Lu, S.; Miles, R. C.; Sakaguchi, S.; Houghton, A. N.; van den Brink, M. R. M.
Article 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-γ and Fas ligand and independent of perform. 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. Copyright © 2006 by The American Association of Immunologists, Inc.
Keywords: controlled study; unclassified drug; nonhuman; cd8 antigen; transcription factor foxp3; mouse; animals; mice; mice, knockout; melanoma; fas ligand; neoplasm proteins; animal experiment; animal model; cell line, tumor; mice, inbred balb c; mice, inbred c57bl; monoclonal antibody; gene activation; gene expression regulation, neoplastic; immunological tolerance; immune tolerance; antibodies, monoclonal; gamma interferon; immunoglobulin g; disease progression; melanoma b16; melanoma, experimental; adoptive transfer; killer cells, natural; tumor immunity; perforin; autoimmunity; t-lymphocyte subsets; graft rejection; cd4 antigen; neoplasm transplantation; tumor growth; adjuvants, immunologic; enzyme linked immunospot assay; fluorescence activated cell sorting; lymphocyte depletion; peptide synthesis; antigens, differentiation; interleukin 2 receptor alpha; natural killer t cell; receptors, tumor necrosis factor; receptors, nerve growth factor; dose-response relationship, immunologic; glucocorticoid induced tumor necrosis factor receptor family related protein; tumor necrosis factor receptor associated factor
Journal Title: Journal of Immunology
Volume: 176
Issue: 11
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2006-06-01
Start Page: 6434
End Page: 6442
Language: English
PUBMED: 16709800
PROVIDER: scopus
DOI: 10.4049/​jimmunol.176.11.6434
DOI/URL:
Notes: --- - "Cited By (since 1996): 79" - "Export Date: 4 June 2012" - "CODEN: JOIMA" - "Source: Scopus"
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