B7-H3/CD276: A Key Co-inhibitory Molecule in Tumor Immune Evasion and a Broad-Spectrum Therapeutic Target

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This article focuses on the molecular characteristics and tumor immune regulatory functions of B7-H3 (CD276), systematically elaborating its structural composition as a B7 family immune checkpoint molecule, its two isoforms, and the generation mechanisms of soluble forms, analyzing its distribution characteristics of low expression in normal tissues and high expression in various malignant tumors and tumor microenvironment stromal components, and exploring the molecular mechanisms by which it promotes tumor proliferation, metastasis, and drug resistance through immune and non-immune pathways.

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B7-H3/CD276: A Key Co-Inhibitory Molecule in Tumor Immune Evasion and a Broad-Spectrum Therapeutic Target

Summary: This article focuses on the molecular characteristics and tumor immune regulatory functions of B7-H3 (CD276), systematically elaborating on its structural composition as an immune checkpoint molecule of the B7 family, its two isoforms, and the generation mechanisms of its soluble form; analyzing its distribution features of low expression in normal tissues and high expression in various malignant tumors and stromal components of the tumor microenvironment; and discussing the molecular mechanisms by which it promotes tumor proliferation, metastasis, and drug resistance through immune and non-immune pathways.

I. The B7 Family and the Molecular Localization of B7-H3.

B7 family proteins are a class of integral membrane proteins discovered on activated antigen-presenting cells. More than 10 B7 protein molecules have been identified to date, including B7-1 (CD80), B7-2 (CD86), and B7-H1 (PD-L1). In immune responses, different B7 molecules deliver co-stimulatory or co-inhibitory regulatory signals. Currently, strategies blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 have achieved major successes in cancer treatment. B7-H3 (also known as CD276) is an important immune checkpoint molecule of the B7 family; its ligand remains unclear, and it is highly expressed in cancer cells, helping them evade surveillance by cytotoxic T cells and natural killer cells. In 2001, B7-H3 was first discovered and identified as a B7 family member, with amino acid homology of 20% to 27% with other B7 family members confirmed. Subsequently, an increasing number of studies have shown that B7-H3 participates in tumor proliferation, metastasis, and therapeutic resistance, leading to poor patient prognosis; therefore, B7-H3 is a highly promising anti-tumor therapeutic target.

II. Molecular Structure and Isoform Composition of B7-H3.

The human B7-H3 gene is located on chromosome 15, encodes 316 amino acids, and has a relative molecular weight of 45 to 66 kDa. B7-H3 is a highly glycosylated type I transmembrane protein composed of an extracellular domain, a transmembrane domain, and a short intracellular domain. B7-H3 has two isoforms: 4IgB7-H3 and 2IgB7-H3. 4IgB7-H3 consists of two pairs of tandemly repeated IgV-like and IgC-like domains, whereas 2IgB7-H3 consists of one pair of IgV-like and IgC-like domains. The predominant isoform expressed on human immune cells and cancer cells is 4IgB7-H3, while mouse B7-H3 expresses only the 2IgB7-H3 isoform. This species difference in isoform expression should be taken into consideration when translating mouse model data to humans.

III. Generation and Function of Soluble B7-H3.

In addition, B7-H3 also includes a soluble form with a molecular weight of approximately 37 kDa; compared with the extracellular domain of 2IgB7-H3, soluble B7-H3 has four additional amino acids encoded by intron sequences at its C-terminus. Soluble B7-H3 may be generated through SRSF3-mediated alternative splicing, cleavage by membrane metalloproteinases, or exosome production. Studies have reported that soluble B7-H3 plays a negative regulatory role in T cell responses, is significantly elevated in the serum of cancer patients, and promotes cancer aggressiveness. The discovery of the soluble form expands the functional dimensions of B7-H3——it not only acts as a membrane-bound molecule exerting regulatory effects at the level of cell contact, but can also mediate long-distance immunosuppressive effects through the circulatory system, providing potential possibilities for its use as a liquid biopsy biomarker.

IV. Expression Distribution of B7-H3 in Normal Tissues and Malignant Tumors.

B7-H3 is expressed at low levels or not expressed in only a few normal tissues. B7-H3 is mainly expressed on the surface of adipocyte progenitor cells, fibroblasts, endothelial cells, osteoblasts, and other cells, with weak staining observed in liver, prostate, uterus, and adrenal gland tissues. This restricted expression pattern provides a potential safety window for targeted therapy.

B7-H3 is highly expressed in a variety of malignant tumors and activated tumor-infiltrating immune cells, and is associated with tumor cell proliferation, metastasis, therapeutic resistance, and poor prognosis. High B7-H3 expression has been detected in various tumor tissues, including lung cancer, breast cancer, prostate cancer, esophageal cancer, ovarian cancer, and hepatocellular carcinoma. Through immunohistochemical staining analysis of tumor tissues from a large number of cancer patients, the overall positive rate of B7-H3 is as high as 60%, and B7-H3 is also highly expressed on stromal fibroblasts and tumor-associated vessels. Compared with tumor cells, B7-H3 expression is higher in cancer stem cells, promoting tumorigenesis, progression, metastasis, and therapeutic resistance. The high expression on stromal fibroblasts and tumor-associated vessels has important therapeutic significance——strategies targeting B7-H3 may exert indirect killing effects on B7-H3-negative tumor cells by disrupting the stromal and vascular support of the tumor microenvironment, thereby expanding the potential beneficiary population.

V. Immune Regulatory Pathways of B7-H3.

B7-H3 plays contradictory roles in the immune system. B7-H3 was initially considered 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 suppresses T cells and promotes tumor invasion. B7-H3 affects immune responses and tumor progression through immune and non-immune pathways.

In terms of immune pathways, in normal human tissues, B7-H3 inhibits T cell activation and proliferation in adaptive immunity. In tumor tissues, B7-H3 inhibits the proliferation of CD4-positive and CD8-positive 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, and dendritic cells, as well as inhibit the secretion of perforin and granzyme B, and by promoting the production of IL-10 and TGF-β1, facilitates the formation of an immunosuppressive microenvironment. This multi-dimensional immunosuppressive spectrum makes B7-H3 an immune evasion driver with extremely broad coverage in the tumor microenvironment.

VI. Non-Immune Pro-Tumor Mechanisms of B7-H3.

In terms of non-immune pathways, during embryogenesis in normal tissues, B7-H3 is highly expressed on osteoblasts and is essential for osteoblast differentiation and bone mineralization. In the tumor microenvironment, B7-H3 promotes migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, and affects tumor cell metabolism. The specific mechanisms include: participating in cancer cell invasion by phosphorylating and activating the PI3K/AKT signaling pathway; upregulating TLR4 expression and inhibiting nuclear factor NF-κB, thereby promoting IL-8 and VEGF expression and promoting cancer cell invasion, metastasis, and angiogenesis; promoting the Ras/Raf/MEK/MAPK signaling pathway and reducing sensitivity to chemotherapeutic drugs; upregulating the JAK2/STAT3 signaling pathway and activating apoptosis inhibitors such as Survivin, Mcl-1, Bcl-xL, and Bcl-2, blocking the caspase cascade and apoptosis initiation to enable tumor cell survival; and regulating glucose metabolism by promoting glycolysis and lactate production through reactive oxygen species-mediated HIF1α stabilization, forming a microenvironment conducive to tumor growth. These non-immune mechanisms, together with immunosuppressive mechanisms, constitute the complete picture of the pro-tumor effects of B7-H3.

VII. Conclusion.

In basic research and targeted drug development related to B7-H3, high-quality recombinant B7-H3 protein is a core tool for elucidating its receptor-binding mechanisms, evaluating the activity of targeted drugs, and conducting species cross-reactivity studies. Cynomolgus monkey-derived B7-H3 protein shares high sequence homology with human B7-H3 and is an important tool molecule for evaluating species cross-reactivity in preclinical toxicology and efficacy assessments. The His tag facilitates efficient purification through immobilized metal affinity chromatography and enables detection and capture via anti-His tag antibodies. To meet the needs of B7-H3 functional research and tumor immunotherapy drug development, Univ provides B7-H3/CD276 His Tag Protein, Cynomolgus. This product is suitable for application scenarios such as binding activity analysis of B7-H3 with targeted antibodies and species cross-reactivity evaluation, in vitro screening of B7-H3-targeted antibody-drug conjugates and bispecific antibodies, research on B7-H3-mediated immunosuppressive mechanisms, and preparation of reference standards in preclinical toxicological evaluation.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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