Nectin-4 is a member of the Nectin family of cell adhesion molecules within the immunoglobulin superfamily. It is unique among Nectins due to its expression patterns and its roles in tumor biology. Nectins are known for their involvement in calcium-independent cell-cell adhesion through both homophilic (same molecule) and heterophilic (different molecules) interactions, contributing significantly to cell junction formation and tissue organization1,3.
APPLICATION NOTE
History of Nectin-4 Discovery
The discovery of Nectin-4 is rooted in the broader identification of the Nectin family, a group of cell adhesion molecules related to the poliovirus receptor (PVR) family. Early studies identified Nectins as crucial components in cellular adhesion, with Nectin-4 later emerging as a unique member due to its distinct expression patterns. Unlike other Nectins, which are broadly present in normal tissues, Nectin-4 was found to be over-expressed selectively in various cancers, marking it a target for oncology research and therapeutic development. Its function as a ligand for TIGIT, a checkpoint receptor on immune cells, was a more recent discovery, revealing Nectin-4’s role in immune suppression within tumors1,2,3.
What Do Nectin-4 Proteins Do?
Nectin-4 proteins play a role in both cell adhesion and immune regulation. As part of the Nectin family, Nectin-4 participates in cell-cell junction formation by binding to other adhesion molecules on adjacent cells, contributing to tissue structure. Its homophilic and heterophilic binding capabilities facilitate stable cellular interactions. In cancer, however, Nectin-4’s over-expression supports tumor growth, invasion, and immune evasion by interacting with immune checkpoint receptors like TIGIT, which inhibits natural killer (NK) and T-cell activity against tumors. These functions make Nectin-4 a dual player in maintaining cellular integrity and, paradoxically, aiding tumor progression1,2,3.
What Does Nectin-4 Stand For?
Nectin-4 stands for “Poliovirus Receptor-Like 4,” reflecting its membership in the poliovirus receptor-related (PVR) protein family. This family, also known as PVR-like (PVRL), includes proteins involved in cell adhesion and immune regulation. Nectin-4 is designated as PVRL4 in the PVR family, which is composed of structurally similar proteins with roles in tissue architecture and immune signaling3.
Nectin-4: Structure, Expression, and Role in Cancer Progression
Molecular Structure
Nectin-4, like other members of the Nectin family, has an extracellular region with three immunoglobulin-like subdomains (V-C-C), a transmembrane domai, and a short cytoplasmic tail. This structure facilitates its role in cell adhesion by forming cis-dimers (on the same cell) or trans-dimers (between cells)1,3. Although all Nectins share structural similarities, Nectin-4’s role as a unique ligand for TIGIT (an immune checkpoint receptor) highlights its distinctive function in immune regulation and tumor immunity2.
Expression and Distribution
Unlike other Nectins, Nectin-4 expression is highly restricted in normal adult tissues, primarily present during fetal development. In adults, its expression re-emerges predominantly in various cancers, including breast, lung, pancreatic, and urothelial carcinomas. This restricted expression pattern makes Nectin-4 a promising biomarker and therapeutic target in oncology3.
Functions and Mechanisms in Cancer
Nectin-4 is implicated in several oncogenic processes, including tumor growth, angiogenesis, and metastasis. It plays a crucial role in promoting cancer cell proliferation and survival through interactions with signaling pathways like PI3K/AKT, which are involved in cell growth and survival.
Tumor Angiogenesis
Nectin-4 promotes blood vessel formation within tumors, enhancing nutrient supply and facilitating tumor expansion. Studies show that it activates the PI3K/AKT signaling pathway, which increases the expression of vascular endothelial growth factor (VEGF), a key promoter of angiogenesis3.
Tumor Cell Growth and Migration
Nectin-4 has been shown to support cancer cell growth and migration, particularly through its influence on epithelial-to-mesenchymal transition (EMT). EMT is a process where cancer cells acquire the ability to migrate and invade other tissues, a fundamental step in metastasis1,3.
Immune Evasion and Checkpoint Interaction
Nectin-4 serves as a ligand for TIGIT, an inhibitory receptor found on T-cells and natural killer (NK) cells. By binding TIGIT, Nectin-4 suppresses immune responses against tumors, allowing cancer cells to evade immune detection. This interaction has made Nectin-4 a target for developing novel cancer immunotherapies2.
Clinical Applications and Therapeutic Potential
Due to its cancer-specific expression, Nectin-4 is considered a valuable biomarker for several tumor types, particularly in advanced or metastatic stages. Nectin-4 expression correlates with poor prognosis and increased metastasis in many cancers, including breast, bladder, and pancreatic cancers. Therapeutics targeting Nectin-4, such as monoclonal antibodies and antibody-drug conjugates, are currently in clinical development to block its interaction with TIGIT, enhance immune response, and reduce tumor growth.
Enfortumab Vedotin
This antibody-drug conjugate (ADC) targets Nectin-4 and has shown efficacy in treating Nectin-4-positive urothelial carcinoma. By delivering a cytotoxic payload directly to cancer cells expressing Nectin-4, it selectively destroys these cells while sparing normal tissues3.
Immune Checkpoint Inhibition
Monoclonal antibodies targeting the Nectin-4-TIGIT axis are under investigation to boost immune responses against Nectin-4-expressing tumors. This approach aims to enhance NK cell and T-cell cytotoxicity, providing a combined effect of immune checkpoint inhibition and cancer specificity2.
Other Notable Names and Characteristics
Nectin-4, also referred to as PVRL4, is part of the larger poliovirus receptor-like (PVR) family. It is distinguished from other Nectin proteins by its selective re-expression in cancerous tissues, making it not only a diagnostic biomarker but also a therapeutic target in oncology3.
Conigen’s Novel Nectin-4 Cis-Dimer: Advancing Cancer Research with Native Quaternary Conformation
Nectin-4 forms a dimer on the cell surface. The available recombinant Nectin-4 proteins on the market are monomeric proteins of the extracellular region which lack the native dimer quaternary structure conformation. The quaternary conformation can be critical target epitopes for therapeutics. The novel Nectin-4 cis-dimer recombinant protein from Conigen is engineered to mimic the native cis-dimer quaternary structure and conformation on the cell surface. It contains the full length extracellular 3 Ig-like domains fused with a novel dimer motif. High quality Nectin-4 cis-dimer protein is produced from HEK 293 cells with a post-translational process similar to natural expressing cells. The Nectin-4 cis-dimer demonstrates significantly enhanced binding to its receptor TIGIT compared to monomeric Nectin-4 protein. This novel Nectin-4 cis-dimer protein can be an advanced antigen for cancer biology research and therapeutics discovery.
References
- Harrison, O., Vendome, J., Brasch, J. et al. Nectin ectodomain structures reveal a canonical adhesive interface. Nat Struct Mol Biol 19, 906–915 (2012). https://doi.org/10.1038/nsmb.2366
- Reches, A., Ophir, Y., Stein, N., Kol, I., Isaacson, B., Charpak Amikam, Y., Elnekave, A., Tsukerman, P., Kucan Brlic, P., Lenac, T., Seliger, B., Jonjic, S., & Mandelboim, O. (2020). Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. Journal for immunotherapy of cancer, 8(1), e000266. https://doi.org/10.1136/jitc-2019-000266
- Liu, Y., Han, X., Li, L., Zhang, Y., Huang, X., Li, G., Xu, C., Yin, M., Zhou, P., Shi, F., Liu, X., Zhang, Y., & Wang, G. (2021). Role of Nectin‑4 protein in cancer (Review). International journal of oncology, 59(5), 93. https://doi.org/10.3892/ijo.2021.5273
