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ICOS

Official Full Name
inducible T cell costimulator
Organism
Homo sapiens
GeneID
29851
Background
The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. [provided by RefSeq, Jul 2008]
Synonyms
AILIM; CD278; CVID1;
Bio Chemical Class
Immunoglobulin
Protein Sequence
MKSGLWYFFLFCLRIKVLTGEINGSANYEMFIFHNGGVQILCKYPDIVQQFKMQLLKGGQILCDLTKTKGSGNTVSIKSLKFCHSQLSNNSVSFFLYNLDHSHANYYFCNLSIFDPPPFKVTLTGGYLHIYESQLCCQLKFWLPIGCAAFVVVCILGCILICWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL
Open
Disease
Lupus erythematosus, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
4 +
Discontinued Drug
0

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Detailed Information

Inducible T cell costimulator (ICOS), also known as CD278, is a protein that plays a significant role in immune responses and cell signaling. Since its discovery in 1999, ICOS has been recognized as an important co-stimulatory receptor in the immune system. It is part of the CD28 family, which includes other co-stimulatory molecules such as CD28 and CTLA-4. ICOS is primarily expressed in activated T cells and plays a crucial role in T cell activation, survival, and differentiation. In this article, we will explore the structure, function, and implications of ICOS in immunity and its potential as a therapeutic target.

Structure and Expression of ICOS

The ICOS gene encodes a protein that belongs to the immunoglobulin superfamily of cell surface receptors. The protein is expressed as a homodimer and is primarily found on activated T cells. The gene encoding ICOS is located on chromosome 2q33 in humans, adjacent to the genes for CD28 and CTLA-4. This clustering suggests that these genes may have evolved from a common ancestor gene and could be regulated synergistically. The protein itself is about 55–60 kDa in size, and its expression is induced upon T cell activation.

Unlike CD28, which is constitutively expressed on T cells, ICOS is inducible and expressed only on activated or memory T cells. Studies have shown that ICOS is not present in resting T cells, but it can be detected in CD4+ and CD8+ T cells after T cell receptor (TCR) activation. The expression of ICOS is regulated by signals from both the TCR and CD28. ICOS expression can be enhanced by co-stimulation via CD28, suggesting an interdependent relationship between these molecules in immune responses.

Figure 1 illustrates the dual role of the CD28/ICOS-ICOSL signaling pathway in both inhibiting and promoting cancer.Figure 1. The anti-cancer and pro-cancer effects of the CD28/ICOS-ICOSL signaling pathway. (Amatore F, et al., 2020)

The Role of ICOS in T Cell Activation and Function

ICOS plays a critical role in the activation and function of T cells, particularly in maintaining effector T cell responses after initial activation. In the early stages of T cell activation, ICOS co-stimulation can promote T cell proliferation and cytokine secretion, including IL-2. However, ICOS is not as essential for the initial T cell activation as CD28. Instead, ICOS becomes crucial in maintaining the function and survival of activated T cells.

Research has shown that ICOS signaling prevents activated T cells from undergoing activation-induced cell death (AICD), which typically occurs after T cells have fulfilled their function. This anti-apoptotic effect ensures that effector T cells remain functional for longer periods, which is essential for sustained immune responses. Moreover, ICOS can enhance the secretion of cytokines like IL-4, IL-5, IL-10, IFN-γ, and TNF-α, which are important for various immune functions.

ICOS in T Cell Differentiation and Immune Responses

ICOS is particularly important in regulating the differentiation of T helper cells (Th cells). Research indicates that ICOS plays a key role in both Th1 and Th2 immune responses. In Th2-dominated responses, ICOS stimulation can enhance the production of cytokines like IL-4 and IL-13. In contrast, in Th1-dominated responses, ICOS also contributes to the secretion of IFN-γ and TNF-α. These findings suggest that ICOS is not restricted to one type of T helper response but is involved in both Th1 and Th2 pathways, influencing the overall immune balance.

The role of ICOS is not limited to T cell responses alone. It is also critical for T/B cell collaboration. ICOS facilitates the interaction between T cells and B cells by promoting the expression of CD154 (CD40 ligand), which is crucial for class switching and the formation of germinal centers in B cells. This T/B interaction is essential for effective antibody production, and defects in ICOS signaling can impair the immune response, leading to conditions like common variable immunodeficiency (CVID).

ICOS and Cancer Immunotherapy

The dual nature of ICOS in immune regulation, both promoting and inhibiting immune responses, has made it a target of interest in cancer immunotherapy. On one hand, ICOS signaling can enhance T cell responses against tumors, promoting the activation of effector T cells that can kill cancer cells. On the other hand, ICOS is also expressed on regulatory T cells (Tregs), which can suppress anti-tumor immune responses.

Therapeutic approaches targeting ICOS have focused on either stimulating its activity to enhance anti-tumor immunity or blocking its function to reduce Treg-mediated immune suppression. ICOS agonists have shown promise in enhancing T cell responses in cancer models, while ICOS antagonists are being developed to inhibit the accumulation of Tregs in the tumor microenvironment. These strategies aim to manipulate the immune system to favor tumor rejection while minimizing immune suppression.

Clinical Development and Potential Therapies

Although there are no approved drugs targeting ICOS yet, several compounds are currently in clinical development. For example, GSK3359609, an ICOS agonist, had progressed to clinical trials but was discontinued in 2021. Other drugs, such as acazicolcept, a dual-target antibody targeting both ICOS and CD28, are being investigated for treating autoimmune diseases like systemic lupus erythematosus (SLE). Vopratelimab, an ICOS-targeted antibody, is being evaluated in cancer immunotherapy trials, and other bispecific antibodies targeting both ICOS and PD-1 are also in early-stage clinical trials.

Table 1. Overview of drugs, targets, and development stages in clinical trials.

Drug NameTargetCompanyDevelopment PhaseIndication
AcazicolceptCD28 & ICOSAlpine Immune SciencesPhase IIArthritis
VopratelimabICOSJounce TherapeuticsPhase IICancer
Sarcophagine-BombesinICOSClarity PharmaceuticalsPhase IICancer, Breast
AtibuclimabICOSIcrosPhase I/IIAcute Lung Injury
Sarcophagine-BombesinICOSClarity PharmaceuticalsPhase I/IICancer, Breast
BMS-986226ICOSBristol-Myers SquibbPhase I/IICancer, Solid Tumor
MocemestrocelICOSSentien BiotechnologiesPhase I/IIAcute Kidney Injury
IzuralimabPD-1 & ICOSXencorPhase ICancer, Solid Tumor
MEDI-570ICOSAstraZenecaPhase IPeripheral T-cell Lymphoma

References:

  1. Marafioti T, Paterson JC, Ballabio E, et al. The inducible T-cell co-stimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation. Haematologica. 2010;95:432-439.
  2. Amatore F, Ortonne N, Lopez M, et al. ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells. Blood Advances. 2020;4(20):5203-5214.
  3. Amatore F, Gorvel L, Olive D. Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy. Expert Opin Biol Ther. 2020;20(2):141-150.
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