Alhamad Salwa, Elmasry Yassmin, Uwagboe Isabel, Chekmeneva Elena, Sands Caroline, Cooper Benjamin W, Camuzeaux Stephane, Salam Ash, Parsons Maddy
Randall Centre for Cell and Molecular Biophysics, King's College London, Guys Campus, New Hunts House, London SE1 1UL, UK.
Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
Cancers (Basel). 2023 Jul 7;15(13):3530. doi: 10.3390/cancers15133530.
Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour-immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings.
肺癌是全球最常见的癌症之一，尽管治疗方案有所改进，但患者预后仍然很差。肺腺癌起源于肺上皮细胞，了解特定的遗传和环境因素如何导致这些细胞发生致癌转化，对于确定促成肿瘤发生的途径至关重要。近年来，免疫疗法在治疗不同癌症方面的应用日益增多，这促使人们探索肿瘤细胞中的免疫调节剂，这些调节剂可能为操控这一过程提供新的靶点。其中，包括程序性死亡受体1（PD-1）在内的B7家族细胞表面受体，因其在调节肿瘤微环境中免疫细胞反应方面的作用而备受关注。B7-H3（CD276）是该家族成员之一，在许多癌症类型中表达上调，并被认为参与肿瘤-免疫相互作用。然而，该受体在正常肺上皮细胞中的功能和配体，以及在缺乏免疫细胞相互作用的情况下，B7-H3过表达调节癌症进展的机制仍不清楚。在此，我们提供证据表明，B7-H3与关键的限速代谢酶肌苷酸脱氢酶2（IMPDH2）相关，并且在高表达B7-H3的人肺癌细胞中，这种复合物的定位发生了改变。从机制上讲，IMPDH2:B7-H3复合物在癌细胞中发挥保护作用，使其免受化疗引发的氧化应激，从而导致细胞存活。我们进一步证明，癌细胞中B7-H3的缺失对二维培养中的生长或迁移没有影响，但以IMPDH2依赖的方式促进三维球体的扩增。这些发现为B7-H3在正常和转化的肺癌细胞代谢稳态中的功能提供了新的见解，虽然该分子仍然是免疫治疗的一个有吸引力的靶点，但这些发现提醒在某些临床环境中使用抗B7-H3疗法时要谨慎。
