Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection

Clouthier, Derek L.; Watts, Tania H.

doi:10.1016/j.cytogfr.2013.12.003

Cited by 82 publications

(79 citation statements)

References 172 publications

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“…Importantly, CD8 T cell expansion was limited to the virus-specific cells and did not produce splenomegaly or liver inflammation, in contrast to the reported effects of anti-4-1BB agonist therapy, which can have pathological effects, including cytokine storm, splenomegaly, and hepatitis (16)(17)(18). Our findings are of particular importance given the recent interest in GITR as a therapeutic target in multiple diseases (20). We find that a single dose of anti-GITR is effective as a stand-alone therapy that has significant effects on viral control, showing durable effects up to 2 wk posttreatment, without overt immune pathology.…”

contrasting

confidence: 41%

“…1). GITR is present at low levels on NK cells and naive and memory T cells and increases on these populations upon activation (20). Consistently, the level of GITR increased on T-bet + Th1 cells, reaching a maximum at day 8 p.i., coinciding with peak LCMV-specific CD8 T cell responses, and returning to baseline by day 21 p.i.…”

Section: Gitrl Is Rapidly Induced On Macrophages and DC Following Lcmmentioning

confidence: 51%

“…2 and reviewed in (20)] made it possible that the effects of DTA-1 on CD8 T cell expansion were indirect due to effects on APC or other immune cells. To evaluate whether DTA-1 was acting intrinsically on the CD8 T cells in this model, we generated CD45.2 GITR +/+ :CD45.1 GITR 2/2 mixed bone marrow chimeras (Fig.…”

Section: Agonistic Anti-gitr Intrinsically Enhances Cd8 T Cell Responmentioning

confidence: 99%

“…GITR has also shown therapeutic potential in cancer and autoimmune murine models, with unique cell-specific and contextdependent effects (20). In 2006, the National Cancer Institute ranked GITR the twelfth most promising immune therapeutic target for cancer.…”

mentioning

confidence: 99%

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Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Clouthier

Zhou

Watts

2014

The Journal of Immunology

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The costimulatory TNFR family member GITR can provide important survival signals for CD8 T cells. However, little is known about the regulation of this pathway during a chronic infection. In this study, we show that GITR ligand (GITRL) is maximally induced on APCs at day 2 post–lymphocytic choriomeningitis virus (LCMV) clone 13 infection, but is downregulated to below baseline levels by day 8 postinfection (p.i.), and remains so at the chronic stage of infection. At its peak, GITRL expression is highest on macrophages, with lower expression on conventional and plasmacytoid dendritic cells. GITR expression was highest on T regulatory cells but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 p.i. and was maintained at low, but above baseline levels at the chronic stage of LCMV infection. As GITRL was limiting at the chronic stage of infection, we investigated the potential of therapeutic stimulation of GITR at this stage using agonistic anti-GITR Ab. Anti-GITR treatment at day 21 p.i. increased the frequency and number of LCMV-specific CD8 T cells, resulting in increased in vivo CTL activity and a concomitant decrease in viral load, despite the persistence of PD-1 expression. These effects of anti-GITR were CD8 T cell intrinsic, with no detectable effects on Th1 or T regulatory cells. In contrast to other TNFR agonists, such as anti–4-1BB, which can cause immune pathology, a single therapeutic dose of anti-GITR did not induce splenomegaly or increase serum alanine transaminase. These studies identify GITR as a promising therapeutic target for chronic infection.

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contrasting

confidence: 41%

Section: Gitrl Is Rapidly Induced On Macrophages and DC Following Lcmmentioning

confidence: 51%

Section: Agonistic Anti-gitr Intrinsically Enhances Cd8 T Cell Responmentioning

confidence: 99%

mentioning

confidence: 99%

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Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Clouthier

Zhou

Watts

2014

The Journal of Immunology

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“…7-10) and natural killer (NK) cells (11)(12)(13). Expression of GITR is significantly increased upon T-cell activation, and ligation of GITR provides a costimulatory signal that positively modulates antigen-specific T-cell responses, leading to enhanced cellular and humoral immunity (11,12,14). The counter structure, GITR-Ligand (GITR-L), is expressed on antigen-presenting cells (dendritic cells, B cells, and macrophages; refs.…”

Section: Introductionmentioning

confidence: 99%

Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells

Sukumar¹,

Wilson²,

Yu³

et al. 2017

Cancer Research

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GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of T reg -mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both na€ ve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a phase I clinical study. Expression of human GITR was comparable with that of mouse GITR in tumor-infiltrating T regs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of T regs in vitro. In human TIL cultures, MK-4166 induced phosphorylation of NFkB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFkB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating T regs , suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the T reg -mediated suppressive tumor microenvironment. Cancer Res; 77(16); 4378-88. Ó2017 AACR.

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Development of a fully human anti‐GITR antibody with potent antitumor activity using H2L2 mice

Tong

Liu²,

Qi³

et al. 2022

FEBS Open Bio

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Glucocorticoid‐induced TNF receptor‐related (GITR) can act as a co‐stimulatory receptor, representing a potential target for safely enhancing immunotherapy efficacy. GITR is triggered by a GITR ligand or an agonist antibody and activates CD8 + and CD4 + effector T cells, reducing tumor‐infiltrating Treg numbers and resulting in activation of immune responses and tumor cell destruction by effector T cells. GITR is an attractive target for immunotherapy, especially in combination therapy with immune checkpoint inhibitors, as is being explored in clinical trials. Using H2L2 transgenic mice encoding the human immunoglobulin variable region and hybridoma technology, we generated a panel of fully human antibodies that showed excellent specific affinity and strong activation of human T cells. After conversion to fully human antibodies and engineering modification, we obtained an anti‐GITR antibody hab019e2 with enhanced antitumor activity in a B‐hGITR MC38 mouse model compared to Tab9H6V3, an anti‐GITR antibody that activates T cells and inhibits Treg suppression from XenoMouse. As a fully human antibody with its posttranslational modification hot spot removed, the hab019e2 antibody exerted more potent therapeutic effects, and may have potential as a novel and developable antibody targeting GITR for follow‐up drug studies.

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Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection

Cited by 82 publications

References 172 publications

Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC

Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells

Development of a fully human anti‐GITR antibody with potent antitumor activity using H2L2 mice

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