Fig. 2

Structures, distributions, interactions and biological functions of B7-H3 and putative receptors. Three proteins have been identified as potential B7-H3 receptors, including TLT-2 (A), IL20RA (B) and PLA2R1 (C). TLT-2 is widely expressed on the surface of myeloid, B and T cells, and its function in specific cell types has been separately studied. TLT-2 plays a proinflammatory role in CD8+ T cells, neutrophils and microglia while reducing the Th1 immune response and blocking Th1 differentiation when activated on monocytes. The effect of B7-H3 binding to TLT-2 on CD8+ T cells is controversial, and the functional interaction between B7-H3 and TLT-2 in other cell types remains unknown (A). Little is known about the specific cell types that express IL20RA and PLA2R1 and their cell type-specific functions. IL20RA activation enhances breast cancer cell stemness and establishes an immunosuppressive TME via the JAK1/STAT3 signaling pathway, while modulation of the TME via the JAK1/STAT3 pathway through IL20RA and IL20RB is still disputed, requiring more robust and direct evidence (B). PLA2R1 has been indicated as a tumor-suppressive regulator that induces breast cancer cell apoptosis and inhibits transformation to renal cell carcinoma (C). Considering the diverse roles of B7-H3 in the TME, other unknown receptors must be reported continuously. Human B7-H3 gene locates in 15q24.1 and has 12 exons encoding 316 amino acids; the structure of B7-H3 (4IgB7-H3 here, the major isoform in humanity) comprises two identical pairs of extracellular lgV-like and IgC-like domains, a transmembrane region and a 45-aa cytoplasmic tail. Seven B7-H family members (B7-H1 to B7-H7) and their receptors expressed on T cells are also displayed, where B7-H3 binds to TLT-2, IL20RA, PLA2R1 and other interesting as yet unknown receptors. “+” in green indicates the immunostimulatory (positive) signal, and “−” in red indicates the immunosuppressive (negative) signal (D). TME, tumor microenvironment