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].