B7-H3 is a 316 amino acid-long type I transmembrane protein, existing in two isoforms determined by its extracellular domain. In mice, the extracellular domain consists of a single pair of immunoglobulin variable (IgV)-like and immunoglobulin constant (IgC)-like domains, whereas in humans it 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 a very limited expression on normal tissues because of its post-transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types (60% of all cancers). [6] The 4Ig-B7-H3 isoform is predominant in cancer.[7]
In non-malignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing 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 possesses non-immunological pro-tumorigenic functions such as promoting migration, invasion, angiogenesis, chemoresistance, epithelial-to-mesenchymal transition, and affecting tumor cell metabolism.[6]
Due to its selective expression on solid tumors, B7-H3 has been the target of several anticancer agents such as enoblituzumab (MGA271),[8]omburtamab, MGD009, MGC018, DS-7300a, and CAR T cells.[6][7]Nanobodies targeting the IgV and IgC domains of B7-H3 have been developed in the laboratory of Mitchell Ho at the NCI, NIH (Bethesda, US). The nanobody-based CAR T cells are active in preclinical models of pancreatic cancer and neuroblastoma and show efficacy against large tumors in mice.[7]
Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, et al. (March 2001). "B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production". Nature Immunology. 2 (3): 269–274. doi:10.1038/85339. PMID11224528. S2CID43480199.
Zhang GB, Chen YJ, Shi Q, Ma HB, Ge Y, Wang Q, et al. (June 2004). "Human recombinant B7-H3 expressed in E. coli enhances T lymphocyte proliferation and IL-10 secretion in vitro". Acta Biochimica et Biophysica Sinica. 36 (6): 430–436. doi:10.1093/abbs/36.6.430. PMID15188059.
Sakthivel P, Wang X, Gharizadeh B, Giscombe R, Pirskanen R, Nyren P, Lefvert AK (December 2006). "Single-nucleotide polymorphisms in the B7H3 gene are not associated with human autoimmune myasthenia gravis". Journal of Genetics. 85 (3): 217–220. doi:10.1007/BF02935335. PMID17406098. S2CID20818492.
