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

B7- h3 （CD276）是一种跨膜受体，也是参与调节肿瘤免疫细胞相互作用的七个B7超家族免疫检查点分子之一。B7-H3在包括肺癌、乳腺癌、结肠癌、肾癌和卵巢癌在内的许多癌症类型中高度过表达。B7-H3是开发治疗药物的一个有吸引力的靶点，这导致了人源化抗B7-H3抗体的开发，这些抗体在临床前研究中延缓了原发性肿瘤的生长，目前正在临床试验中。然而，B7-H3在癌细胞中的生理配体和功能尚不清楚。帕森斯实验室最近未发表的研究表明，B7-H3定位于人肺癌细胞-细胞连接处，并有助于肌动蛋白的组织和癌细胞的侵袭。我们进一步表明，在正常肺上皮细胞中，B7-H3定位于纤毛，并且B7-H3的过度表达（如在癌细胞中所见）导致纤毛形成的丧失。此外，我们的分析表明，B7H3的缺失导致关键代谢酶活性的改变和氧化应激的上调，B7H3的高表达可能保护癌细胞免受化疗和应激诱导的细胞死亡。B7-H3也定位于称为棒和环的结构，这是主要由IMPDH2聚合物组成的特定细胞质结构。我们进一步发现B7-H3的胞内结构域可以与GTP从头合成中的限速酶IMPDH2结合。GTP是代谢能量的关键来源，参与蛋白质合成和一些信号级联反应，特别是参与细胞生长和侵袭的Rho GTP酶。然而，由B7-H3驱动的信号通路以及它们与肿瘤微环境合作促进肿瘤发生的潜在途径仍不清楚。

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 Recent unpublished work in the Parsons lab has shown that B7-H3 localises to human lung carcinoma cell-cell junctions and contributes to actin organisation and cancer cell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.