Contactin-4 (CNTN4) (CNTN4)

Contactin-4 (CNTN4) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein and a member of the immunoglobulin superfamily (UniProt Q8IWV2). While traditionally known for its role in axonal guidance and synaptic plasticity within the central nervous system, recent research has identified CNTN4 as a novel immune checkpoint ligand (Compugen Ltd., 2020). In the tumor microenvironment, CNTN4 is expressed by various cancer cells and interacts with the Amyloid Precursor Protein (APP) expressed on the surface of T cells (SITC, 2020). This interaction triggers an inhibitory signal that suppresses T-cell proliferation, activation, and the production of pro-inflammatory cytokines, thereby facilitating tumor immune evasion (PubMed: 33172914). Therapeutic development focuses on monoclonal antibodies designed to block the CNTN4-APP interaction, aiming to reinvigorate the immune response against "cold" tumors or those resistant to existing PD-1/PD-L1 therapies. Given its expression in the brain, potential safety concerns include neurological side effects, alongside the general risk of autoimmunity associated with checkpoint inhibitors.

Other names

BIG-2Axonal-associated cell adhesion moleculeBrain-derived immunoglobulin superfamily protein 2

Blockade of the inhibitory interaction between CNTN4 on tumor cells and Amyloid Precursor Protein (APP) on T cells to enhance anti-tumor immune response.