Laboratory for Molecular and Cellular Therapy, Department Biomedical Science, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
Int J Mol Sci. 2021 Aug 13;22(16):8691. doi: 10.3390/ijms22168691.
Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of and are significantly decreased in lung adenocarcinoma patients, while the / balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.
肿瘤坏死因子-α（TNFα）可以结合两种不同的受体（TNFR1/2）。跨膜形式（tmTNFα）优先与 TNFR2 结合。在 TNF-α 转化酶（TACE）切割 tmTNFα 后，其可溶性（sTNFα）形式被释放，与 TNFR1 的亲和力更高。这种组合使 TNFα 在肿瘤细胞存活（凋亡）和抗肿瘤免疫刺激（抑制）、血管生成和转移等过程中具有多种相反的作用。本文综述了 TNFα 的功能及其作为预测癌症进展和对免疫治疗反应的生物标志物的潜力，重点关注肺癌。通过挖掘现有测序数据，我们进一步证明 在肺腺癌患者中的表达水平显著降低，而 / 平衡增加。我们得出结论，单独使用 TNFα 作为生物标志物的潜力不太可能提供确凿的发现，但 TACE 可能与 sTNFα/tmTNFα 以及 TNFR1/TNFR2 的微妙平衡一起发挥关键作用，因此强调了对联合 TNFα 通路调节剂与免疫疗法治疗肺癌患者的合理化治疗方案进行更多研究的重要性。
