Regulation of cancer cell behaviour and tumorigenesis by B7-H3.

B7-H3 (CD276) is a transmembrane receptor and one of seven B7 superfamily immune checkpoint molecules involved in regulating tumour-immune cell interactions. B7-H3 is highly overexpressed in many cancer types including lung, breast, colon, renal, and ovarian. B7-H3 is an appealing target for the development of therapeutic agents, and this has resulted in the development of humanized anti-B7-H3 antibodies that delay the growth of primary tumours in preclinical studies and are now in clinical trials. However, the physiological ligand and functions of B7-H3 in cancer cells remain unknown. Recent unpublished work in the Parsons lab has shown that B7-H3 localises to human lung carcinoma cell-cell junctions and contributes to actin organisation and cancer cell invasion. We have further shown that B7-H3 localises to cilia in normal lung epithelial cells, and that overexpression of B7-H3 (as seen in cancer cells) leads to loss of cilia formation. Moreover, our analysis has revealed that loss of B7H3 leads to altered activity of key metabolic enzymes and upregulation of oxidative stress, and high expression of B7H3 may protect cancer cells from chemotherapy and stress-induced cell death. B7-H3 also localises to structures called rods & rings, which are specific cytoplasmic structures comprised predominantly of IMPDH2 polymers. We have further shown that the intracellular domain of B7-H3 can associate with IMPDH2, which is the rate limiting enzyme in the de novo synthesis of GTP. GTP is a key source of metabolic energy and is involved in protein synthesis and several signalling cascades, particularly Rho GTPases that are involved in cell growth and invasion. However, the signalling links that are driven by B7-H3 and the potential ways in which these co-operate with the tumour microenvironment to promote tumorigenesis remain unknown.