CD96

Official Full Name

CD96 molecule

Organism

Homo sapiens

GeneID

10225

Background

The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein. The protein may play a role in the adhesive interactions of activated T and NK cells during the late phase of the immune response. It may also function in antigen presentation. Alternative splicing generates multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

Synonyms

TACTILE;

Protein Sequence

MEKKWKYCAVYYIIQIHFVKGVWEKTVNTEENVYATLGSDVNLTCQTQTVGFFVQMQWSKVTNKIDLIAVYHPQYGFYCAYGRPCESLVTFTETPENGSKWTLHLRNMSCSVSGRYECMLVLYPEGIQTKIYNLLIQTHVTADEWNSNHTIEIEINQTLEIPCFQNSSSKISSEFTYAWSVENSSTDSWVLLSKGIKEDNGTQETLISQNHLISNSTLLKDRVKLGTDYRLHLSPVQIFDDGRKFSCHIRVGPNKILRSSTTVKVFAKPEIPVIVENNSTDVLVERRFTCLLKNVFPKANITWFIDGSFLHDEKEGIYITNEERKGKDGFLELKSVLTRVHSNKPAQSDNLTIWCMALSPVPGNKVWNISSEKITFLLGSEISSTDPPLSVTESTLDTQPSPASSVSPARYPATSSVTLVDVSALRPNTTPQPSNSSMTTRGFNYPWTSSGTDTKKSVSRIPSETYSSSPSGAGSTLHDNVFTSTARAFSEVPTTANGSTKTNHVHITGIVVNKPKDGMSWPVIVAALLFCCMILFGLGVRKWCQYQKEIMERPPPFKPPPPPIKYTCIQEPNESDLPYHEMETL

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

Comprising the immunoglobulin superfamily (IgSF), the CD96 gene codes for a type I membrane protein. Highly expressed in T cells and natural killer (NK) cells, this protein could help these cells adhere during later phases of immunological responses. Additionally important in antigen presentation might be CD96. Alternately splicing allows CD96 to generate many transcript variants encoding distinct isoforms. Particularly for its possible use in cancer immunotherapy, CD96 has attracted more and more interest recently as an immune checkpoint molecule.

Molecular Structure and Function of CD96

The CD96 protein consists of an extracellular domain, a flexible neck region, a transmembrane domain, and a cytoplasmic domain. CD96, a member of IgSF, consists of three immunoglobulin (Ig) domains. Whereas subtype 2 loses the 16 amino acids encoded by exon 4 in the second Ig domain, generating a type I or C domain, human CD96 subtype 1 has three components consisting of V, V, and C domains. Like other IgSF members, CD96 has a transmembrane domain; its cytoplasmic domain has a proline-rich area, an immune receptor tyrosine inhibitory motif (ITIM), and a YXXM motif lacking in mouse CD96.

Rich in serine, threonine, and proline, CD96's neck region is also very glycosylated and usually has many O-glycosylated disaccharide molecules. Specifically in the latter phases of immune responses, CD96 controls the adhesion between NK cells and target cells by interacting with CD155 (PVR). Control of the function and immune cell migration to areas of inflammation depends on the interaction between CD96 and CD155.

CD96's Role in Immune Response

Particularly in the latter phases of immunological responses, CD96 is crucial in the activation of T cells and NK cells. Once within endothelial cells, these immune cells connect to the blood vessel wall via integrins and selectins then travel towards sick or inflammatory areas. Employing its association with PVR (CD155), CD96 drives NK cell adherence to target cells, therefore facilitating an important function in anti-tumor immune responses.

Furthermore, CD96 creates intricate immune regulating systems with other immune molecules such as TIGIT and CD226. Along with CD96, both TIGIT and CD226 are also members of IgSF and help to reduce immunity. By binding to CD155, CD96 rivals TIGIT to have a negative regulating impact on immune responses. Competitive dynamic binding produced by the various affinities of the receptors CD96, TIGIT, CD226, and their ligands is fundamental for immune evasion by cancer cells.

Figure 1 describes how antagonistic and agonistic antibodies interact with immune checkpoints and co-stimulatory molecules to regulate T cell function and anti-tumor immunity, highlighting key receptor-ligand pairs and inter-relationships within the immune system. Figure 1. Antagonistic antibodies block inhibitory immune checkpoints to enhance T cell function, survival, and proliferation by preventing receptor-ligand interactions. (Yin N, et al., 2024)

CD96's Potential in Cancer Immunotherapy

Cancer treatment has made great strides with immunotherapy using immune checkpoint inhibitors like PD-1 and CTLA-4 inhibitors. Still, these treatments have difficulties including limited response rates, side effects, and opposition. Consequently, investigating novel immune checkpoint molecules to improve treatment effectiveness has taken the front stage in research.

Rising as a crucial target in cancer immunotherapy as an immune checkpoint molecule is CD96. Together with TIGIT and CD226, CD96 controls the anti-tumor actions of T cells and NK cells, therefore reducing their functions. By use of inhibitors, targeting CD96 helps to efficiently restore the immune system's capacity to clear tumors and therefore alleviate immune suppression.

The development of many medications aiming at CD96 is in progress. GSK's monoclonal antibody Nelistotug (GSK-6097), for instance, is under clinical trials and has been combined with other immune checkpoint inhibitors, such as PD-1 and TIGIT, to treat head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Agenus has created BMS-986442 (AGEN1777), a strengthened bispecific antibody aiming against TIGIT and CD96. Currently in the trial stage, this medication is being utilized to boost T cell activation by combining with the PD-1 inhibitor nivolumab.

References:

Feng S, Isayev O, Werner J, et al. CD96 as a Potential Immune Regulator in Cancers. Int J Mol Sci. 2023 Jan 9;24(2):1303.
Trumet L, Weber M, Hahn A, et al. The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer? Cancers (Basel). 2023 Apr 2;15(7):2126.
Yin N, Li X, Zhang X, et al, Niedermann G, Lu Y, Xue J. Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities. Signal Transduct Target Ther. 2024 May 22;9(1):126.

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