B7-H3的表达调控分子机理及其靶向抗肿瘤研究

近些年，B7-H3被越来越多的研究报道在多种肿瘤组织呈高表达，而在正常组织低或不表达，同时研究也表明该分子具有抑制T细胞激活的功能，因此B7-H3被认为是非常有前景的广谱肿瘤抗原和治疗靶标。然而，至今B7-H3的受体，功能，及表达调控机制等诸多方面尚未明确，严重阻碍针对其开展靶向治疗研究。前期，本课题组围绕B7-H3开展了表达谱，单抗制备，双特异抗体，CAR-T细胞制备及靶向抗肿瘤研究等系列研究工作。我们发现B7-H3在多种肿瘤组织中虽呈高表达，但表达异质性很强，而且B7-H3靶向的CAR-T治疗会导致靶点表达下调，从而导致肿瘤复发。重要的，我们发现一些小分子抗肿瘤靶向药的使用能够上调B7-H3的表达，将其与B7-H3的靶向生物制剂联用可以起到协同抗肿瘤的效果。因此，本研究将深入开展其表达调控机制，功能及联合治疗研究，为针对B7-H3的靶向抗肿瘤策略推向临床奠定基础。

In recent years, B7-H3 has been reported by more and more research to be highly expressed in a variety of tumor tissues, but low or not expressed in normal tissues. Moreover, studies have shown that the molecule has the function of inhibiting T-cell activation. Thus, B7-H3 is considered as a very promising broad-spectrum tumor antigen and therapeutic target. However, so far, the receptors, functions, expression regulation mechanisms and many other aspects of B7-H3 are not clear, hindering the development of B7-H3-targeted therapy research. We have carried out a series of research works related to B7-H3, such as its expression spectrum, monoclonal antibody generation, bi-specific antibody, CAR-T cell preparation, and targeted anti-tumor research. We found that B7-H3 was highly expressed in a variety of tumor tissues, but the expression was highly heterogeneous, and treatment with B7-H3-targeted CAR-T led to a reduction in target expression, which led to tumor recurrence. Importantly, we found that the usage of some small-molecule anti-tumor drugs can increase the expression of B7-H3, and its combination with B7-H3-target biologic drugs had a synergistic anti-tumor effect. Therefore, the current project will explore the expression regulation mechanism, molecular function and combination therapy of B7-H3. Our study will provide valuable information for translating B7-H3-based targeted therapy into clinical practice.