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].