Kanchan Ranjana K, Doss David, Khan Parvez, Nasser Mohd Wasim, Mahapatra Sidharth
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; School of Medicine, Creighton University, Omaha, NE 68178, USA.
Biochim Biophys Acta Rev Cancer. 2022 Sep;1877(5):188783. doi: 10.1016/j.bbcan.2022.188783. Epub 2022 Aug 24.
Targeting the anti-tumor immune response via the B7 family of immune-regulatory checkpoint proteins has revolutionized cancer treatment and resulted in punctuated responses in patients. B7-H3 has gained recent attention given its prominent deregulation and immunomodulatory role in a multitude of cancers. Numerous cancer studies have firmly established a strong link between deregulated B7-H3 expression and poorer outcomes. B7-H3 has been shown to augment cancer cell survival, proliferation, metastasis, and drug resistance by inducing an immune evasive phenotype through its effects on tumor-infiltrating immune cells, cancer cells, cancer-associated vasculature, and the stroma. Given the complex interplay between each of these components of the tumor microenvironment, a deeper understanding of B7-H3 signaling properties is inherently crucial to developing efficacious therapies that can target and inhibit these cancer-promoting interactions. This review delves into the various ways B7-H3 acts as an immunomodulator to facilitate immune evasion and promote tumor growth and spread. With post-transcriptional and post-translational modifications giving rise to different active isoforms coupled with recent discoveries of its putative receptors, B7-H3 can perform diverse functions. Here, we first discuss the dual co-stimulatory/co-inhibitory functions of B7-H3 in the context of normal physiology and cancer. We then discuss the crosstalk facilitated by B7-H3 between stromal components and tumor cells that promote tumor growth and metastasis in different populations of tumor cells, associated vasculature, and the stroma. Concurrently, we highlight therapeutic strategies that can exploit these interactions and their associated limitations, concluding with a special focus on the promise of next-gen in silico-based approaches to small molecule inhibitor drug discovery for B7-H3 that may mitigate these limitations.
通过免疫调节检查点蛋白的B7家族靶向抗肿瘤免疫反应，彻底改变了癌症治疗方式，并在患者中产生了阶段性反应。鉴于B7-H3在多种癌症中显著失调且具有免疫调节作用，最近受到了关注。大量癌症研究已确凿地证实，B7-H3表达失调与较差的预后之间存在紧密联系。研究表明，B7-H3通过影响肿瘤浸润免疫细胞、癌细胞、癌症相关脉管系统和基质，诱导免疫逃避表型，从而增强癌细胞的存活、增殖、转移和耐药性。鉴于肿瘤微环境中这些成分之间复杂的相互作用，深入了解B7-H3信号特性对于开发能够靶向和抑制这些促癌相互作用的有效疗法至关重要。本综述深入探讨了B7-H3作为免疫调节剂促进免疫逃避、肿瘤生长和扩散的各种方式。由于转录后和翻译后修饰产生了不同的活性异构体，再加上最近对其假定受体的发现，B7-H3可以发挥多种功能。在这里，我们首先讨论B7-H3在正常生理和癌症背景下的双重共刺激/共抑制功能。然后，我们讨论B7-H3在基质成分和肿瘤细胞之间促进肿瘤生长和转移的串扰，这些肿瘤细胞、相关脉管系统和基质存在于不同群体中。同时，我们强调可以利用这些相互作用的治疗策略及其相关局限性，最后特别关注基于下一代计算机方法发现B7-H3小分子抑制剂药物的前景，这可能会减轻这些局限性。
