3.1 ICOS (Inducible T-cell CO-Stimulator)
Inducible T-cell CO-Stimulator (ICOS, cluster of differentiation (CD278)), a member of the IgSF, is a pivotal co-stimulatory receptor expressed on activated T cells (activated CD4 and CD8 T cells), belonging to the CD28 family of molecules. ICOS is also constitutively expressed by FOXP3+CD25+CD4+ Treg [278]. ICOS was first identified in humans and shortly after in mice [279, 280]. It shares significant homology with the co-stimulatory molecule CD28 and the immune-attenuator CTLA-4 [279]. It plays a crucial role in regulating immune responses by providing additional signals that amplify T cell activation and function [279, 280].
ICOS is typically up-regulated following T cell activation and interacts with its ligand, ICOS ligand (ICOSL), primarily expressed on antigen-presenting cells (APCs) such as dendritic cells, macrophages, B cells,  and somatic cells, including tumour cells in the TME.  [281, 282, 283, 284]. The interaction between ICOS and ICOSL elicits a range of activities across different T cell subpopulations, including T cell activation and effector functions. When this interaction is prolonged, it also mediates suppressive activities through regulatory T cells. [285]. The ICOS/ICOSL axis may influence both anti-tumor T cell responses and pro-tumor responses due to its association with the suppressive activity of Tregs, thus exhibiting a dual effect [286]. The signaling pathway triggered by ICOS engagement leads to enhanced production of cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and interferon-gamma (IFN-γ), which are critical for shaping immune responses [285].
In the context of cancer immunotherapy, ICOS/ICOSL axis has been demonstrated to promote anti-tumor T cell responses when activated in Th1 and other Teff cells, or to promote protumor responses when triggered in Tregs [285, 287]. Combining ICOS agonists with ICIs, such as antibodies targeting PD-1 or CTLA-4, have shown to potentiate the effect of inhibitory checkpoint blockade in preclinical studies [288, 289]. A study by Fan et al. observed that in mouse models of melanoma and prostate cancer, simultaneous CTLA-4 blockade and ICOS engagement through tumor cell vaccines engineered to express the ICOS ligand enhanced antitumor immune responses both quantitatively and qualitatively, significantly improving tumor rejection [288]..Both agonistic (GSK3359609, JTX-2011) and antagonistic (MEDI-570, KY1044) monoclonal antibodies (mAbs) targeting the ICOS/ICOSL pathway are being explored for cancer immunotherapy in clinical trials [285]. INDUCE-2 (NCT03693612) a Phase I/II, open-label clinical trial, in patients with advanced solid tumors, anti-ICOS agonist (feladilimab) , administered alone or combined with an anti-CTLA-4 antibody tremelimumab, showed promising outcomes in tolerability, toxicity profile, but showed limited efficacy [290]. The Phase I/II ICONIC Trial investigated the ICOS agonist Vopratelimab, both as a monotherapy and in combination with nivolumab, in patients with advanced solid tumors. The trial demonstrated a favorable safety profile for Vopratelimab alone and in combination with nivolumab, particularly in patients with high ICOS CD4 T-cell populations [291]. ICOS mAbs are unlikely to be used as monotherapy because they do not independently induce satisfactory cytotoxic immune responses [285].