Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8⁺ and CD4⁺ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.

Keywords: anti-GITR monoclonal antibodies; cancer; glucocorticoid-induced TNFR-related protein (GITR); hepatocellular carcinoma (HCC); immunotherapy.

Figure 1

(A) TNFR superfamily types: costimulatory receptors, death domain receptors and decoy receptors, along with their basic promoting-inhibiting activity, (B) GITR and GITRL genes’ structure in exons (C) GITR/GITRL main effects in the various types of immune cells and their general pattern of tumorigenic activity. (CD: cytoplasmic domain; CRD: cysteine-rich domain; DC: dendritic cell, DCR3: decoy receptor 3; ED: extracellular domain; GITR: glucocorticoid-induced tumor necrosis factor receptor; NF-κB: nuclear factor kappa-light-chain enhancer; NK-cell: natural-killer cell; OPG: osteoprotegerin receptor; TD: transmembrane domain; Tregs: T regulatory cells; TNFR-TNFR1/2: tumor necrosis factor receptors; TRAIL: tumor necrosis factor-related apoptosis inducing-ligand).

Figure 2

Schematic presentation of HCC immune network interactions and anti-GITR treatment in cancer immunotherapy, as monotherapy or combined with other antibodies (anti-PD-1, anti-CTLA-4). T cells, NK cells and DCs present a positive effect in immune tumor rejection, while Tregs, macrophages and neutrophils present a negative effect. In order to use targeted therapy, HCC cells should show antigen expression through gene mutations neoAgs or TAAs. Antibodies targeting CTLA-4 result in a reduction of immunosuppressive activity via increased recovery of T-cell function. This result is enhanced when anti-CTLA-4 therapy is combined with anti-GITR antibody. Anti-GITR therapy also results in an increase in cytokine reduction and proliferation, similar to anti-PD-1 and anti-PD-L1 targeting, decreasing tumor growth. However, combined anti-GITR and anti-PD-1 targeting has now yet shown a significant reduction of tumor growth compared to anti-GITR and anti-PD-1 monotherapy. (APC: antigen-presenting cell; CTLA-4: cytotoxic T lymphocyte-associated antigen 4; DC: dendritic cell; GITR: glucocorticoid-induced tumor necrosis factor receptor; GITRL: glucocorticoid-induced tumor necrosis factor receptor ligand; IL-8: interleukin 8; MHC: major histocompability complex; NK cell: natural killer cell; PD-1: programmed cell-death protein-1 PD-L1: programmed cell-death protein-1 ligand; TCR: T-cell receptor, TGFβ: tumor growth factor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor).

Figure 3

Schematic presentation of anti-Gal-9 anti-HCC effect and anti-Gal-9/anti-GITR combination treatment. PD-1 interacts with Gal-9 and TIM-3 to inhibit the apoptosis of T cells, expressing both PD-1 and TIM-3 and competes with TIM-3 for binding to Gal-9, attenuating TIM-3-mediated cell death signals and promoting T cell survival. Anti-Gal-9/anti-GITR combination treatment leads to enhanced expansion of CD8⁺ T cells and depletion of Treg cells within the HCC TME. (CD4: cytoplasmic domain 4; DC: dendritic cell; Gal-9: galectin-9, GITR: glucocorticoid-induced tumor necrosis factor receptor; MHCII: major histocompatibility complex 2; TCR: T cell receptor; TIM-3: T cell immunoglobin and mucin domain containing-3; Treg: T regulatory cell; PD-1: program cell death protein-1).