ICOS (CD278)

Target id: 2939

Nomenclature: ICOS (CD278)

Family: Other immune checkpoint proteins, CD molecules

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	199	2q33.2	ICOS	inducible T cell costimulator	3
Mouse	1	200	1 30.6 cM	Icos	inducible T cell co-stimulator
Rat	1	200	9q32	Icos	inducible T-cell co-stimulator

Previous and Unofficial Names
inducible T-cell costimulator \| activation-inducible lymphocyte immunomediatory molecule \| AILIM \| CVID1 \| inducible costimulator

Database Links
Alphafold	Q9Y6W8 (Hs), Q9WVS0 (Mm), Q9R1T7 (Rn)
ChEMBL Target	CHEMBL3712953 (Hs)
Ensembl Gene	ENSG00000163600 (Hs), ENSMUSG00000026009 (Mm), ENSRNOG00000046196 (Rn)
Entrez Gene	29851 (Hs), 54167 (Mm), 64545 (Rn)
Human Protein Atlas	ENSG00000163600 (Hs)
KEGG Gene	hsa:29851 (Hs), mmu:54167 (Mm), rno:64545 (Rn)
OMIM	604558 (Hs)
Pharos	Q9Y6W8 (Hs)
RefSeq Nucleotide	NM_012092 (Hs), NM_017480 (Mm), NM_022610 (Rn)
RefSeq Protein	NP_036224 (Hs), NP_059508 (Mm), NP_072132 (Rn)
UniProtKB	Q9Y6W8 (Hs), Q9WVS0 (Mm), Q9R1T7 (Rn)
Wikipedia	ICOS (Hs)

Natural/Endogenous Ligands
ICOS ligand {Sp: Human}

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Antibodies

Key to terms and symbols

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Antibody		Sp.	Action	Value	Parameter	Reference
feladilimab		Monkey	Binding	9.0	pK_d	4
⤷	pK_d 9.0 (K_d 9.5x10^-10 M) [4]
feladilimab		Hs	Binding	8.9	pK_d	4
⤷	pK_d 8.9 (K_d 1.34x10^-9 M) [4]

Immunopharmacology Comments
Inducible T cell costimulator (ICOS) and it's ligand constitute an immune checkpoint. ICOS is a surface receptor on activated T cells that binds its ligand on antigen presenting cells. Ligand-receptor interaction is a T cell activation signal. ICOS is a major regulator of the adaptive immune reponse that is structurally and functionally related to CD28 [3]. One of the major regulators of ICOS expression is Roquin-1 (RC3H1; Q5TC82), an E3 ubiquitin ligase that contributes to the maintenance of immune homeostasis by regulating the expression of a number of immunoregulatory proteins [7]. Roquin-mediated reduction in ICOS mRNA levels results in repression of autoimmunity, and conversley a loss-of-function mutation in mouse Rc3h1 increases T cell Icos expression which leads to an accumulation of lymphocytes and an associated lupus-like autoimmune syndrome [9]. ICOS is being investigated as an immuno-oncology drug target. Agonist-like binding of anti-ICOS monoclonal antibodies (mAbs) to ICOS expressed on tumour infiltrating CD4-positive T cells stimulates ICOS-positive T cell proliferation, enhances cytotoxic T-lymphocyte (CTL) survival and increases CTL-mediated immune responses against tumour cells. Anti-ICOS mAbs such as JTX-2011 and GSK3359609 are being evaluated in early stage clinical trials as either monotherapy or in combination with other immune checkpoint inhibitor mAbs vs. various solid tumour types (JTX-2011: Phase 1/2 NCT02904226 ±anti-PD-1 checkpoint inhihbitor nivolumab; feladilimab (GSK3359609): Phase 2/3 NCT04128696 ±anti-PD-1 checkpoint inhihbitor pembrolizumab). In July 2021, GSK announced that they were terminating development of feladilimab due to lack of efficacy detected at interim analysis of their Phase 2 lung cancer study NCT03739710.

Immunopharmacology Comments

Inducible T cell costimulator (ICOS) and it's ligand constitute an immune checkpoint. ICOS is a surface receptor on activated T cells that binds its ligand on antigen presenting cells. Ligand-receptor interaction is a T cell activation signal. ICOS is a major regulator of the adaptive immune reponse that is structurally and functionally related to CD28 [3]. One of the major regulators of ICOS expression is Roquin-1 (RC3H1; Q5TC82), an E3 ubiquitin ligase that contributes to the maintenance of immune homeostasis by regulating the expression of a number of immunoregulatory proteins [7]. Roquin-mediated reduction in ICOS mRNA levels results in repression of autoimmunity, and conversley a loss-of-function mutation in mouse Rc3h1 increases T cell Icos expression which leads to an accumulation of lymphocytes and an associated lupus-like autoimmune syndrome [9].

ICOS is being investigated as an immuno-oncology drug target. Agonist-like binding of anti-ICOS monoclonal antibodies (mAbs) to ICOS expressed on tumour infiltrating CD4-positive T cells stimulates ICOS-positive T cell proliferation, enhances cytotoxic T-lymphocyte (CTL) survival and increases CTL-mediated immune responses against tumour cells. Anti-ICOS mAbs such as JTX-2011 and GSK3359609 are being evaluated in early stage clinical trials as either monotherapy or in combination with other immune checkpoint inhibitor mAbs vs. various solid tumour types (JTX-2011: Phase 1/2 NCT02904226 ±anti-PD-1 checkpoint inhihbitor nivolumab; feladilimab (GSK3359609): Phase 2/3 NCT04128696 ±anti-PD-1 checkpoint inhihbitor pembrolizumab). In July 2021, GSK announced that they were terminating development of feladilimab due to lack of efficacy detected at interim analysis of their Phase 2 lung cancer study NCT03739710.

Cell Type Associations

Immuno Cell Type:	T cells
Cell Ontology Term:	effector T cell (CL:0000911)
Comment:	ICOS is upregulated on effector and memory T cells during activation. It is also present on peripheral Tregs.
References:	1,5,8

Immuno Process Associations

Immuno Process:

T cell (activation)

Immuno Process:

Immune regulation

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Immuno Process:

Immune system development

Clinically-Relevant Mutations and Pathophysiology

Disease:

Common variable immunodeficiency

Description:	CVID is a group of genetically heterogeneous primary immunodeficiencies. Whilst a small number of cases can be linked to deficiency in a single gene (see the OMIM links as examples), the cause is likely to be polygenic in the majority of cases. Symptoms vary between patients, but CVID is generally characterised by a failure to produce antibodies (hypogammaglobulinemia) and therefore susceptibility to recurrent infections and inflammation (including autoimmunity).
Disease Ontology:	DOID:12177
OMIM:	613495, 607594, 606453, 240500, 613493
Orphanet:	ORPHA1572

Role:

Homozygous mutation in the ICOS gene is known to cause common variable immunodeficiency type 1 (CVID1; OMIM: 607594).

References:

2,6

General Comments
ICOS belongs to the CD28 and CTLA-4 cell-surface receptor family. It is active as homodimers and is a costimulatory molecule involved in cell-cell signaling, innate immune responses, and regulation of cell proliferation.

References

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1. Beier KC, Hutloff A, Dittrich AM, Heuck C, Rauch A, Büchner K, Ludewig B, Ochs HD, Mages HW, Kroczek RA. (2000) Induction, binding specificity and function of human ICOS. Eur J Immunol, 30 (12): 3707-17. [PMID:11169414]

2. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW et al.. (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol, 4 (3): 261-8. [PMID:12577056]

3. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA. (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature, 397 (6716): 263-6. [PMID:9930702]

4. Liu Y-b, Parmar RS, Mayes P, Olive D. (2016) Agonistic icos binding proteins. Patent number: WO2016120789A1. Assignee: Glaxosmithkline Intellectual Property Development Limited, Inserm (Institut National De La Sante Et De La Recherche Medicale), Institut Jean Paoli & Irene Calmettes, Universite D'aix-Marseille, Centre National De La Recherche Scientifique. Priority date: 28/01/2015. Publication date: 04/08/2016.

5. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity, 12 (4): 431-40. [PMID:10795741]

6. Salzer U, Maul-Pavicic A, Cunningham-Rundles C, Urschel S, Belohradsky BH, Litzman J, Holm A, Franco JL, Plebani A, Hammarstrom L et al.. (2004) ICOS deficiency in patients with common variable immunodeficiency. Clin Immunol, 113 (3): 234-40. [PMID:15507387]

7. Schaefer JS, Klein JR. (2016) Roquin--a multifunctional regulator of immune homeostasis. Genes Immun, 17 (2): 79-84. [PMID:26673963]

8. Vocanson M, Rozieres A, Hennino A, Poyet G, Gaillard V, Renaudineau S, Achachi A, Benetiere J, Kaiserlian D, Dubois B et al.. (2010) Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells. J Allergy Clin Immunol, 126 (2): 280-9, 289.e1-7. [PMID:20624644]

9. Yu D, Tan AH, Hu X, Athanasopoulos V, Simpson N, Silva DG, Hutloff A, Giles KM, Leedman PJ, Lam KP et al.. (2007) Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature, 450 (7167): 299-303. [PMID:18172933]

How to cite this page

Other immune checkpoint proteins: ICOS (CD278). Last modified on 02/08/2021. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2939.

ICOS (CD278)

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References

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