Abstract
GITR is a type I transmembrane protein with significant homology, particularly within the cytoplasmic domain, to other tumor necrosis factor (TNF) receptor family members such as 4-1BB, OX40, and CD27. Initially identified following dexamethasone treatment of a murine T cell hybridoma line (Nocentini et al. 1997), GITR was subsequently characterized in human lymphocytes as a 241 amino acid, 25 kDa protein encoded by the TNFSFR18 gene on chromosome 1p36. Since its identification, preclincal studies have demonstrated that ligation of GITR with agonist antibodies could results in clearance of established tumors. This has lead to interest in GITR as a target for immunotherapy with multiple agents currently in phase 1 development.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Coe D, Begom S, Addey C, White M, Dyson J, Chai JG. Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol Immunother. 2010;59:1367–77.
Cohen AD, Diab A, Perales MA, et al. Agonist anti-GITR antibody enhances vaccine-induced CD8+ T-cell responses and tumor immunity. Cancer Res. 2006;66:4904–12.
Cohen AD, Schaer DA, Liu C, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:e10436.
Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74.
Esparza EM, Arch RH. Glucocorticoid-induced TNF receptor functions as a costimulatory receptor that promotes survival in early phases of T cell activation. J Immunol. 2005;174:7869–74.
Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.
Gurney AL, Marsters SA, Huang RM, et al. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol. 1999;9:215–8.
Hanabuchi S, Watanabe N, Wang YH, et al. Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL). Blood. 2006;107:3617–23.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.
Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009;113:3546–52.
Kanamaru F, Youngnak P, Hashiguchi M, et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol. 2004;172:7306–14.
Kim 2015 (Nature Medicine 21, 1010–1017 (2015) doi:10.1038/nm.3922)
Ko K, Yamazaki S, Nakamura K, et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med. 2005;202:885–91.
Ko HJ, Kim YJ, Kim YS, et al. A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res. 2007;67:7477–86.
Liu B, Li Z, Mahesh SP, et al. Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis. J Biol Chem. 2008;283:8202–10.
Liu Z, Tian S, Falo Jr LD, Sakaguchi S, You Z. Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation. Mol Ther. 2009;17:1274–81.
McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16:311–23.
Mitsui J, Nishikawa H, Muraoka D, et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res. 2010;16:2781–91.
Muriglan SJ, Ramirez-Montagut T, Alpdogan O, et al. GITR activation induces an opposite effect on alloreactive CD4(+) and CD8(+) T cells in graft-versus-host disease. J Exp Med. 2004;200:149–57.
Nishikawa H, Kato T, Hirayama M, et al. Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. Cancer Res. 2008;68:5948–54.
Nocentini G, Giunchi L, Ronchetti S, et al. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A. 1997;94:6216–21.
Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116:1935–45.
Ramirez-Montagut T, Chow A, Hirschhorn-Cymerman D, et al. Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J Immunol. 2006;176:6434–42.
Ronchetti S, Nocentini G, Riccardi C, Pandolfi PP. Role of GITR in activation response of T lymphocytes. Blood. 2002;100:350–2.
Ronchetti S, Zollo O, Bruscoli S, et al. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol. 2004;34:613–22.
Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–43.
Schaer 2013 : (Cancer Immunol Res November 2013 1; 320).
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3:135–42.
Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini R, Riccardi C. GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. Cell Death Differ. 2002;9:1382–4.
Stephens GL, McHugh RS, Whitters MJ, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol. 2004;173:5008–20.
TolerRx I. Agonistic antibodies to human glucocorticoid-induced tumor necrosis factor receptor as potential stimulators of T cell immunity for the treatment of cancer and viral infections. Expert Opin Ther Patents. 2007;17:567–75.
Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A. 2003;100:15059–64.
Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200:771–82.
Zhou P, L’Italien L, Hodges D, Schebye XM. Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J Immunol. 2007;179:7365–75.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this entry
Cite this entry
Wolchok, J., Cohen, A., Schaer, D. (2017). Glucocorticoid-Induced TNF Receptor (GITR). In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0717-2_6
Download citation
DOI: https://doi.org/10.1007/978-1-4419-0717-2_6
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-0716-5
Online ISBN: 978-1-4419-0717-2
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences