Medler Juliane, Kucka Kirstin, Wajant Harald
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Auvera Haus, Grombühlstrasse 12, 97080 Würzburg, Germany.
Cancers (Basel). 2022 May 25;14(11):2603. doi: 10.3390/cancers14112603.
Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8 T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.
尽管肿瘤坏死因子（TNF）阻滞剂在自身免疫性疾病治疗中取得了巨大成功，且TNF被确定为在多种方面影响肿瘤发生发展的一个因素，但长期以来，肿瘤坏死因子受体2（TNFR2）在肿瘤生物学中的作用及其作为癌症治疗中潜在治疗靶点的适用性一直被低估。随着TNFR2被确定为调节性T细胞（Treg）刺激因子以及免疫治疗方法取得总体临床突破，这种情况已从根本上得到改变。然而，仅将TNFR2视为肿瘤微环境中的单一免疫抑制因子是不够的。TNFR2还可以共刺激CD8 T细胞，使一些免疫细胞和肿瘤细胞对TNFR1的细胞毒性作用敏感，和/或充当癌基因。鉴于TNFR2在癌症相关方面具有广泛的活性，TNFR2拮抗剂和激动剂都被考虑用于肿瘤治疗，并且在临床前研究中确实显示出压倒性的抗肿瘤活性，这并不奇怪。基于对TNFR2信号传导和TNFR2免疫调节功能的简要总结，我们在此讨论使用TNFR2激动剂和拮抗剂获得的主要临床前研究结果和见解。特别是，我们探讨了哪些与TNFR2相关的分子和细胞机制是TNFR2激动剂和拮抗剂所观察到的抗肿瘤活性的基础这一问题。
