Journal Article
. 2006 May; 176(11):6434-42.
doi: 10.4049/jimmunol.176.11.6434.

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

Teresa Ramirez-Montagut 1 Andrew Chow  Daniel Hirschhorn-Cymerman  Theis H Terwey  Adam A Kochman  Sydney Lu  Randy C Miles  Shimon Sakaguchi  Alan N Houghton  Marcel R M van den Brink  
  • PMID: 16709800
  •     58 citations


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.

Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection.
Adriano Boasso, Monica Vaccari, +7 authors, Claire Chougnet.
J Virol, 2007 Aug 24; 81(21). PMID: 17715231    Free PMC article.
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.
Baoying Liu, Zhuqing Li, +4 authors, Robert B Nussenblatt.
J Biol Chem, 2008 Jan 31; 283(13). PMID: 18230609    Free PMC article.
A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.
Xiao-Tong Song, Kevin Evel-Kabler, +3 authors, Si-Yi Chen.
Nat Med, 2008 Mar 04; 14(3). PMID: 18311150    Free PMC article.
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
Silvia Piconese, Barbara Valzasina, Mario P Colombo.
J Exp Med, 2008 Mar 26; 205(4). PMID: 18362171    Free PMC article.
Highly Cited.
Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states.
Zhaocai Zhou, Xiaomin Song, +6 authors, Mark I Greene.
Proc Natl Acad Sci U S A, 2008 Apr 02; 105(14). PMID: 18378892    Free PMC article.
Immune rejection of mouse tumors expressing mutated self.
Fei Duan, Yun Lin, +8 authors, Alan N Houghton.
Cancer Res, 2009 Apr 09; 69(8). PMID: 19351857    Free PMC article.
Therapeutic immunity by adoptive tumor-primed CD4(+) T-cell transfer in combination with in vivo GITR ligation.
Zuqiang Liu, Shenghe Tian, +2 authors, Zhaoyang You.
Mol Ther, 2009 May 07; 17(7). PMID: 19417739    Free PMC article.
Enhancement of T-cell-mediated anti-tumour immunity via the ectopically expressed glucocorticoid-induced tumour necrosis factor receptor-related receptor ligand (GITRL) on tumours.
Jinhua Piao, Yosuke Kamimura, +8 authors, Miyuki Azuma.
Immunology, 2009 Jul 17; 127(4). PMID: 19604302    Free PMC article.
GITR Blockade Facilitates Treg Mediated Allograft Survival.
Samsher B Sonawane, James I Kim, +9 authors, James F Markmann.
Transplantation, 2009 Nov 26; 88(10). PMID: 19935370    Free PMC article.
Key role of the GITR/GITRLigand pathway in the development of murine autoimmune diabetes: a potential therapeutic target.
Sylvaine You, Lynn Poulton, +8 authors, Lucienne Chatenoud.
PLoS One, 2009 Nov 26; 4(11). PMID: 19936238    Free PMC article.
Integrating costimulatory agonists to optimize immune-based cancer therapies.
Angela D Pardee, Amy K Wesa, Walter J Storkus.
Immunotherapy, 2010 Jan 05; 1(2). PMID: 20046961    Free PMC article.
GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells.
Gongxian Liao, Sushrusha Nayak, +7 authors, Cox Terhorst.
Int Immunol, 2010 Feb 09; 22(4). PMID: 20139172    Free PMC article.
Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody.
Jose F Ponte, Paul Ponath, +7 authors, Michael Rosenzweig.
Immunology, 2010 Mar 06; 130(2). PMID: 20201988    Free PMC article.
An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand.
Dawei Cui, Shengjun Wang, +8 authors, Huaxi Xu.
Cell Mol Immunol, 2010 Mar 17; 7(4). PMID: 20228835    Free PMC article.
Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation.
Adam D Cohen, David A Schaer, +10 authors, Jedd D Wolchok.
PLoS One, 2010 May 11; 5(5). PMID: 20454651    Free PMC article.
Highly Cited.
Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells.
A-S Bergot, A Durgeau, +3 authors, D Klatzmann.
Cancer Gene Ther, 2010 May 15; 17(9). PMID: 20467452    Free PMC article.
Modulation of CTLA-4 and GITR for cancer immunotherapy.
Francesca Avogadri, Jianda Yuan, +2 authors, Jedd D Wolchok.
Curr Top Microbiol Immunol, 2010 Jun 22; 344. PMID: 20563707    Free PMC article.
Glucocorticoid-induced TNFR-related (GITR) protein and its ligand in antitumor immunity: functional role and therapeutic modulation.
Theresa Placke, Hans-Georg Kopp, Helmut Rainer Salih.
Clin Dev Immunol, 2010 Oct 12; 2010. PMID: 20936139    Free PMC article.
3G11 expression in CD4+ T cell-mediated autoimmunity and immune tolerance.
Fang Zhou, Guang-Xian Zhang, Abdolmohamad Rostami.
Int Immunopharmacol, 2010 Nov 19; 11(5). PMID: 21084064    Free PMC article.
Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens.
Anik L Côté, Peisheng Zhang, +5 authors, Mary Jo Turk.
J Immunol, 2010 Nov 26; 186(1). PMID: 21106849    Free PMC article.
ISCOMATRIX vaccines mediate CD8+ T-cell cross-priming by a MyD88-dependent signaling pathway.
Nicholas S Wilson, Becky Yang, +13 authors, Eugene Maraskovsky.
Immunol Cell Biol, 2011 Sep 07; 90(5). PMID: 21894173    Free PMC article.
Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells.
Scott K Pruitt, David Boczkowski, +5 authors, Smita Nair.
Eur J Immunol, 2011 Oct 27; 41(12). PMID: 22028176    Free PMC article.
Pharmacological modulation of GITRL/GITR system: therapeutic perspectives.
Giuseppe Nocentini, Simona Ronchetti, Maria Grazia Petrillo, Carlo Riccardi.
Br J Pharmacol, 2011 Oct 28; 165(7). PMID: 22029729    Free PMC article.
The dendritic cell-regulatory T lymphocyte crosstalk contributes to tumor-induced tolerance.
Nona Janikashvili, Bernard Bonnotte, Emmanuel Katsanis, Nicolas Larmonier.
Clin Dev Immunol, 2011 Nov 24; 2011. PMID: 22110524    Free PMC article.
Modulation of GITR for cancer immunotherapy.
David A Schaer, Judith T Murphy, Jedd D Wolchok.
Curr Opin Immunol, 2012 Jan 17; 24(2). PMID: 22245556    Free PMC article.
Advances in targeting cell surface signalling molecules for immune modulation.
Sheng Yao, Yuwen Zhu, Lieping Chen.
Nat Rev Drug Discov, 2013 Feb 02; 12(2). PMID: 23370250    Free PMC article.
Highly Cited. Review.
Generation and preclinical characterization of a Fc-optimized GITR-Ig fusion protein for induction of NK cell reactivity against leukemia.
Benjamin Joachim Schmiedel, Antje Werner, +4 authors, Helmut Rainer Salih.
Mol Ther, 2013 Feb 06; 21(4). PMID: 23380816    Free PMC article.
Agonist antibodies to TNFR molecules that costimulate T and NK cells.
Ignacio Melero, Daniel Hirschhorn-Cymerman, +2 authors, Jedd D Wolchok.
Clin Cancer Res, 2013 Mar 06; 19(5). PMID: 23460535    Free PMC article.
Highly Cited.
Immune modulation by chemotherapy or immunotherapy to enhance cancer vaccines.
Genevieve M Weir, Robert S Liwski, Marc Mansour.
Cancers (Basel), 2011 Jan 01; 3(3). PMID: 24212948    Free PMC article.
GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.
David A Schaer, Sadna Budhu, +8 authors, Jedd D Wolchok.
Cancer Immunol Res, 2014 Jan 15; 1(5). PMID: 24416730    Free PMC article.
Highly Cited.
Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs.
Lei Lu, Xiaobing Xu, +3 authors, Xuan Wang.
J Transl Med, 2014 Feb 08; 12. PMID: 24502656    Free PMC article.
Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice.
Judith T Murphy, Andre P Burey, +4 authors, Jedd D Wolchok.
Blood, 2014 Feb 22; 123(14). PMID: 24558202    Free PMC article.
The "Trojan Horse" approach to tumor immunotherapy: targeting the tumor microenvironment.
Delia Nelson, Scott Fisher, Bruce Robinson.
J Immunol Res, 2014 Jun 24; 2014. PMID: 24955376    Free PMC article.
p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression.
Yong Lu, Mingjun Zhang, +9 authors, Qing Yi.
Nat Commun, 2014 Jun 25; 5. PMID: 24957461    Free PMC article.
Enhanced CD8 T cell responses through GITR-mediated costimulation resolve chronic viral infection.
Maria Fernanda Pascutti, Sulima Geerman, +6 authors, Martijn A Nolte.
PLoS Pathog, 2015 Mar 05; 11(3). PMID: 25738498    Free PMC article.
Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells.
Simona Ronchetti, Erika Ricci, +4 authors, Carlo Riccardi.
J Immunol Res, 2015 May 12; 2015. PMID: 25961057    Free PMC article.
Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells.
Il-Kyu Kim, Byung-Seok Kim, +13 authors, Chang-Yuil Kang.
Nat Med, 2015 Aug 19; 21(9). PMID: 26280119
Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response.
Manisha Pathak, Pankaj Sharma, +3 authors, Shailja Misra-Bhattacharya.
Immunology, 2015 Oct 27; 147(2). PMID: 26501838    Free PMC article.
Regulatory T cells in the immunotherapy of melanoma.
Zhengxiao Ouyang, Hongwei Wu, +3 authors, Gang Huang.
Tumour Biol, 2015 Oct 31; 37(1). PMID: 26515336
Combination strategies to enhance the potency of monocyte-derived dendritic cell-based cancer vaccines.
Ronald J Fecek, Walter J Storkus.
Immunotherapy, 2016 Sep 09; 8(10). PMID: 27605069    Free PMC article.
Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma.
Darrin V Bann, Daniel G Deschler, Neerav Goyal.
Cancers (Basel), 2016 Sep 27; 8(10). PMID: 27669306    Free PMC article.
Combination GITR targeting/PD-1 blockade with vaccination drives robust antigen-specific antitumor immunity.
Daniel O Villarreal, Diana Chin, +2 authors, Linda A Snyder.
Oncotarget, 2017 Apr 08; 8(24). PMID: 28388572    Free PMC article.
Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma.
Bozena Scirka, Edyta Szurek, +4 authors, Arkadiusz Miazek.
Arch Immunol Ther Exp (Warsz), 2017 Jun 24; 65(6). PMID: 28638937    Free PMC article.
Intratumoral delivery of tumor antigen-loaded DC and tumor-primed CD4+ T cells combined with agonist α-GITR mAb promotes durable CD8+ T-cell-dependent antitumor immunity.
Zuqiang Liu, Xingxing Hao, +5 authors, Zhaoyang You.
Oncoimmunology, 2017 Jul 07; 6(6). PMID: 28680744    Free PMC article.
Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy.
Rajeev Shrimali, Shamim Ahmad, +7 authors, Samir N Khleif.
J Immunother Cancer, 2017 Aug 16; 5(1). PMID: 28807056    Free PMC article.
Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy.
Susannah C Shissler, Michael S Lee, Tonya J Webb.
Front Immunol, 2017 Nov 23; 8. PMID: 29163518    Free PMC article.
Identification of key genes implicated in the suppressive function of human FOXP3+CD25+CD4+ regulatory T cells through the analysis of time‑series data.
Xiaofeng Bai, Hua Shi, +3 authors, Shuxiong Xu.
Mol Med Rep, 2017 Dec 30; 17(3). PMID: 29286140    Free PMC article.
A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.
Prabhakaran Kumar, Palash Bhattacharya, Bellur S Prabhakar.
J Autoimmun, 2018 Sep 04; 95. PMID: 30174217    Free PMC article.
Combination immune checkpoint blockade as an effective therapy for mesothelioma.
Vanessa S Fear, Caitlin Tilsed, +10 authors, Scott A Fisher.
Oncoimmunology, 2018 Oct 06; 7(10). PMID: 30288361    Free PMC article.
Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism.
Jaina M Patel, Zhihua Cui, +2 authors, Hong-Ming Hu.
J Immunother Cancer, 2019 Nov 22; 7(1). PMID: 31747946    Free PMC article.
New emerging targets in cancer immunotherapy: the role of GITR.
Giulia Buzzatti, Chiara Dellepiane, Lucia Del Mastro.
ESMO Open, 2020 Aug 21; 4(Suppl 3). PMID: 32817129    Free PMC article.
Turning the Tide Against Regulatory T Cells.
SeongJun Han, Aras Toker, Zhe Qi Liu, Pamela S Ohashi.
Front Oncol, 2019 May 07; 9. PMID: 31058083    Free PMC article.
Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable.
Kellsye P Fabian, Anthony S Malamas, +6 authors, James W Hodge.
Cancer Immunol Res, 2020 Dec 24; 9(2). PMID: 33355290    Free PMC article.
Evaluation of glucocorticoid-induced TNF receptor (GITR) expression in breast cancer and across multiple tumor types.
Mayanne M T Zhu, Samantha Burugu, +5 authors, Torsten O Nielsen.
Mod Pathol, 2020 May 01; 33(9). PMID: 32350416
Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies.
Isabelle Serr, Maria Kral, Martin G Scherm, Carolin Daniel.
Front Immunol, 2021 Mar 09; 12. PMID: 33679808    Free PMC article.
scConnect: a method for exploratory analysis of cell-cell communication based on single cell RNA sequencing data.
Jon E T Jakobsson, Ola Spjuth, Malin C Lagerström.
Bioinformatics, 2021 May 12;. PMID: 33974001    Free PMC article.
Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness.
Daniel Hirschhorn, Allison Betof Warner, +11 authors, Jedd D Wolchok.
JCI Insight, 2021 Oct 23; 6(20). PMID: 34676831    Free PMC article.
Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.
Changhao He, Rachana R Maniyar, +8 authors, Joel R Meyerson.
Sci Adv, 2022 Feb 26; 8(8). PMID: 35213218    Free PMC article.