Definition

B7-H3 (CD276), an immune checkpoint molecule and a co-stimulatory/co-inhibitory immunomodulatory protein that plays a dual role in the immune system, was discovered in the cDNA library of dendritic cells in 2001. B7-H3 is a 316-amino acid-long type I transmembrane protein with two isoforms based on its extracellular domain. In mice, the extracellular domain consists of a pair of immunoglobulin-variable (IgV)-like and immunoglobulin-constant (IgC)-like domains, while in humans, the extracellular domain consists of one pair (2Ig-B7-H3) or two identical pairs (4Ig-B7-H3) due to exon duplication. B7-H3 mRNA is expressed in most normal tissues. In contrast, B7-H3 protein has very limited expression in normal tissues due to posttranscriptional regulation by microRNAs. However, the B7-H3 protein is highly expressed in many different cancer types, accounting for 60% of all cancers.

B7-H3 mRNA is widely present in many tissues of the human body, such as the heart, prostate, pancreas, liver, colon, thymus, etc., while the B7-H3 protein is rarely expressed in normal tissues, which may be related to post-transcriptional regulation. Compared to normal tissues, B7-H3 is highly expressed in many tumor tissues, such as non-small cell lung cancer, gastric cancer, colon cancer, breast cancer, prostate cancer, and head and neck cancer. The difference in expression of B7-H3 at the mRNA level and protein level suggests that there may be a strict post-transcriptional regulatory mechanism that inhibits protein expression.

Fig.1 Structure of B7-H3 protein. A: 4IgB7-H3 which comprises two identical pairs of IgV-like and IgC-like domains.

4IgB7-H3 is the predominant isoform in humans. B: 2IgB7-H3 which comprises a single pair of IgV-like

and IgC-like domains. C: B7-H3 in mouse is expressed only as the 2IgB7-H3 isoform.

Function

In non-malignant tissues, B7-H3 plays a major inhibitory role in adaptive immunity, inhibiting T cell activation and proliferation. In malignant tissues, B7-H3 is an immune checkpoint molecule that inhibits tumor antigen-specific immune responses. B7-H3 also has non-immuno-pro-tumor functions, such as promoting migration, invasion, angiogenesis, chemotherapy resistance, epithelial mesenchymal transformation, and affecting tumor cell metabolism.

In addition to regulating the activation of T cells, B7-H3 also has an effect on other immune cells. Studies have found that B7-H3 is overexpressed in macrophages and DCs in liver cancer patients, and both human and mouse B7-H3 can inhibit NK cell activation, and DC-induced NK cell activation without B7-H3 is more significant, suggesting that B7-H3 may play a role through the body's innate immunity.

B7-H3 Mechanism of Action

B7-H3 plays a contradictory role in the immune system. B7-H3 was originally thought to be a co-stimulatory molecule that stimulates T cells and promotes the secretion of cytokines such as IFN-γ and IL-12. However, most current studies describe B7-H3 as a co-inhibitory molecule that inhibits T cells to promote tumor invasion. B7-H3 affects immune response and tumor progression through immune and non-immune pathways.

Immune Pathway

In human normal tissues, B7-H3 inhibits T cell activation and proliferation in adaptive immunity. In tumor tissues, B7-H3 inhibits the proliferation of CD4+ and CD8+ T cells and reduces the production of IL-2 and IFN-γ. In addition, B7-H3 can also inhibit the activity of NK cells, macrophages, neutrophils, dendritic cells, inhibit the secretion of perforin and granzyme B, and promote the production of IL-10 and TGF-β1, which is conducive to the formation of immunosuppressive microenvironment.

Non-immune Pathway

In normal tissues, B7-H3 is highly expressed on osteoblasts during embryogenesis and is critical for osteoblast differentiation and bone mineralization.

In the tumor microenvironment, B7-H3 promotes migration and invasion, angiogenesis, chemotherapy resistance, and endothelial cell transition to the stromal (EMT), as well as affecting tumor cell metabolism.

1. Activate the PI3K/AKT signaling pathway through phosphorylation to participate in the invasion of cancer cells;

2. Up-regulate TLR4 expression, inhibit nuclear factor NF-κB, and then promote IL-8 and VEGF expression, promote cancer cell invasion, metastasis and angiogenesis;

3. Promote the Ras/Raf/MEK/MAPK signaling pathway and reduce the sensitivity to chemotherapy drugs;

4. Upregulate the JAK2/STAT3 signaling pathway, activate apoptosis inhibitors (such as Survivin, Mcl-1, Bcl-xL and Bcl-2), block the caspase cascade and apoptosis initiation, and survive tumor cells;

5. Regulate glucose metabolism, promote glycolysis and lactic acid increase through ROS-mediated HIF1α stabilization, and form a microenvironment conducive to tumor growth.

Clinical Application

B7-H3 has been extensively studied in a variety of cancers, including but not limited to breast, lung, ovarian, brain, gastric, and squamous cell carcinoma. Its presence is associated with worsening prognosis, poor survival, and relapse rates. Immunotherapy has been active in the first line of tumor treatment together with surgery, radiotherapy and chemotherapy. Abnormal expression of B7-H3 in tumors is associated with tumor immune evasion, tumor growth, invasion and metastasis, so B7-H3 can be used as a new target for tumor immunotherapy.

Alpha Lifetech Inc. is dedicated to developing B7-H3 diagnostic regents. Alpha Lifetech Inc. is a reputable supplier focusing on research, manufacture and sales of In Vitro Diagnostic (IVD) regents. All the IVD regents offered by Alpha Lifetech Inc. have undergone strict QC validation and are certified by the COA (certificate of analysis). Meanwhile, we can provide customized services according to customers' requirements. Alpha Lifetech Inc. is committed to supplying high-quality, high-sensitivity antigen and antibody products for scientific research and industrial customers. In addition to regular small packages, Alpha Lifetech Inc.'s large-scale fermentation platform also allows us to provide raw material-grade IVD regents for the majority of industrial clients.

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