3.4 GITR (Glucocorticoid-Induced TNF Receptor)
Glucocorticoid-Induced TNF Receptor (GITR, TNFRSF18, and CD357), is a
co-stimulatory receptor expressed on various immune cells, including
activated T cells and Tregs. Its expression can be upregulated upon T
cell activation, and it plays a critical role in modulating immune
responses [317]. In the context of Tregs, GITR seems to be a marker
of active Tregs, indicated by its expression linked with other Treg
activation markers or suppressive cytokines (e.g., TGF-β and IL-10), the
existence of GITR+ cells in tissues with active Tregs (e.g., solid
malignancies), or via. functional studies on Tregs [317].
GITR interacts with its ligand, GITR ligand (GITRL), which is expressed
on APCs, endothelial cells, and other immune cells [318]. This
interaction delivers co-stimulatory signals to T cells, promoting their
activation, proliferation, and effector functions. GITR signaling
enhances the production of cytokines such as interleukin-2 (IL-2),
interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), which
are essential for promoting immune responses against pathogens and
tumors [319]. One of the distinctive features of GITR is its
expression on Tregs, a subset of T cells that play a crucial role in
maintaining immune tolerance and preventing autoimmunity. Activation of
GITR on Tregs can lead to their functional modulation, potentially
reducing their suppressive activity and enhancing anti-tumor immunity
mediated by effector T cells [320, 321]. According to Ronchetti et
al., “GITR activation impacts Treg/effector cell interplay in four
distinct ways: (1) temporary inhibition of Treg regulatory activity, (2)
reduced sensitivity of effector T cells to Treg suppression, (3) killing
of Tregs (particularly within solid tumors), and (4) enhanced
proliferation and expansion of the Treg compartment” [317].
In the context of cancer immunotherapy, GITR has emerged as a promising
target. Agonistic antibodies or other agents that activate GITR have
been developed and are under investigation in preclinical and clinical
studies. These GITR agonists aim to boost anti-tumor immune responses by
overcoming immune suppression mediated by Tregs within the TME
[322]. Also by stimulating GITR on activated T cells and modulating
Tregs, GITR agonists can enhance T cell proliferation, cytokine
secretion, and cytotoxic activity against cancer cells [322, 323]. A
study by Amoozgar et al. concluded that, although immune checkpoint
blockers (ICBs) have been unsuccessful in all Phase III glioblastoma
(GBM) trials due to Treg activities, targeting GITR in Treg cells with
an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation
into CD4 effector T cells, reduces Treg cell-mediated suppression of the
anti-tumor immune response, and induces potent anti-tumor effector cells
in GBM [324]. A study by Schoenhals et al. revealed that GITR
Therapy Overcomes Radiation-Induced Treg Immunosuppression and leads to
enhanced effects of radiotherapy , in two tumor 344SQR murine models
[325]. Clinical trials are evaluating GITR agonists as monotherapy
and in combination with other immunotherapies, such as ICIs (e.g.,
anti-PD-1, anti-CTLA-4 antibodies). AMG 228 (NCT02437916), BMS-986156
(NCT02598960), MEDI1873 (NCT02583165), and GWN323 (NCT02740270) are
various GITR mAbs currently in clinical trials [326]. The
first-in-human Phase 1 trial ( NCT01239134 ) of GITR agonism using the
anti-GITR antibody TRX518 demonstrated that it is safe and produces
significant immune effects in patients with incurable cancer. The trial
team further indicated that there is mechanistic preclinical evidence
supporting the rational combination of GITR agonism with checkpoint
blockade [327].