CD226 Immune Checkpoint Molecule for Drug Development

Overview of CD226

CD226 (also known as DNAM-1, TLiSA1, PTA-1) is a costimulatory receptor expressed on NK cells, T lymphocytes, monocytes, and B cells. CD226 is a transmembrane glycoprotein containing two immunoglobulin V-like domains (D1 and D2), an intracellular domain, and a type I transmembrane domain. The extracellular part of CD226 contains two Ig-like domains, and its cytoplasmic tail contains three tyrosine residues. CD226 ligands are identified as PVR (CD155) and Nectin-2 (CD112). Studies on the expression of CD226 in NK cells indicate that its interaction with ligands on tumor cells plays an important role against different types of cancer.

Fig. 1 Mechanisms of T cell immunoreceptor with TIGIT inhibition of CD226. (Chiang and Ira, 2022)Fig. 1 Mechanisms of T cell immunoreceptor with TIGIT inhibition of CD226.1

Structure of CD226

Structural analysis shows that the extracellular D1 domain of CD226 binds to PVR through a conserved docking mode. Whether the D2 domain of CD226 is essential for its binding to PVR needs further investigation. The solution binding affinity measured between human PVR-Fc and CD226-Fc is similar to that between nectin-2-Fc and CD226-Fc. However, compared with PVR expressing cells, the binding efficiency of CD226-Fc to nectin-2 is lower, which indicates that the homologous interaction of actin-2 might hinder the binding of CD226 to nectin-2.

CD226 in Tumor Immunity

The importance of the CD226-PVR (TIGIT/CD155) axis in regulating tumor immunity has been confirmed in preclinical mouse models in vitro and in vivo. CD8+ T cells or DX5+ (CD49b) NK cells isolated from CD226-deficient mice are less cytotoxic to PVR-expressing tumor cells and less cytotoxic to PVR-negative tumor cells. Consistent with the in vitro results, CD226-deficient mice also show a more significant tumor burden on various tumors than wild-type (WT) mice. In lung metastasis mouse models, CD226 deletion leads to impaired NK-cell-mediated tumor growth inhibition. The anti-CD226 blocking monoclonal antibody can be used to study the inhibiting effect of the CD226-PVR axis on the anti-tumor immune response.

Services at Creative Biolabs

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  1. Chiang, Eugene Y., and Ira Mellman. TIGIT-CD226-PVR axis: Advancing immune checkpoint blockade for cancer immunotherapy. Journal for Immunotherapy of Cancer. 10.4 (2022).

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