Inducible co-stimulator (ICOS, CD278), a specific T cell costimulatory molecule of the CD28/CTLA-4 family mainly expressed by CD4 T cells, is a co-stimulator of proliferation and cytokine production by these cells. ICOSL, the unique ligand of ICOS, is constitutively expressed on APCs and can be induced in nonlymphoid tissues under inflammatory conditions. ICOSL has an important co-stimulation role in EC-mediated T cell activation, especially in the reactivation of effector/memory T cells on the endothelium.
ICOS has a low expression on naïve T-cell but is rapidly induced after TCR and/or CD28 engagement to deliver a positive co-stimulatory signal. ICOS signaling is initiated upon engagement by its unique ligand, ICOSL. The binding of ICOSL to ICOS triggers distinct intracellular signaling cascades. These signaling pathways deliver the co-stimulatory signals that promote T cell activation, proliferation, and differentiation. ICOS has a dual role in oncogenesis.
On the one hand, ICOS provides CD8+ T-cell response enhancement, one of the main anti-tumoral mechanisms induced by the ICOS/ICOSL pathway. On the other hand, the ICOS signaling also exhibits pro-tumoral features related to the induction of regulatory T cells (Treg) immunosuppressive activity through the secretion of TGF-β and IL-10. Therefore, ICOS/ICOSL pathway plays an important role in regulating the disease state of many human diseases and may become a key point in therapies.
Fig.1 The role of ICOS and ICOSL. (Amatore, 2020)
Preclinical and Clinical Development of Drugs for ICOS and ICOSLG Pathway
The ICOS/ICOSL axis has been shown to play two opposite final roles in promoting either anti-tumor T cell responses (when activated in Th1 and other Teff) or pro-tumor responses when triggered in Tregs. Therefore, therapeutic modulation of the ICOS/ICOSL pathway should theoretically use either an agonistic and antagonistic monoclonal Ab (mAb), depending on the tumor itself and its microenvironment.
Various studies have demonstrated that anti-tumor T cell responses in mice can be significantly boosted by combining cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade with ICOS engagement. The important role played by ICOS in the effectiveness of CTLA-4 blockade suggests that providing an agonistic stimulus for the ICOS pathway during anti-CTLA-4 therapy might increase its effectiveness. Thus, ICOS is a stimulatory checkpoint that provides a novel target for combining agonistic antibodies with immune checkpoint inhibitors.
ICOS antagonistic antibodies have shown limited anti-tumor activity via their abrogation of Treg-mediated immune suppression, thereby potentially enhancing CTL-mediated immune responses directed to tumor cells. Therefore, depleting the tumor infiltrated Tregs with ICOS/ICOSL antagonists might also be a promising immunotherapy strategy.
Currently, some antagonistic and agonistic mAbs for ICOS/ICOSL pathway are being investigated in clinical trials.
Fig.2 Targeting regulatory and/or effector T cells with ICOS agonistic or antagonistic antibodies. (Solinas, 2020)
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