Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University of Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, The Netherlands; David H. Koch Center for Applied Research of Genitourinary Cancers, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Cancer Genomics Centre Netherlands (CGC.nl), Utrecht University, Utrecht, The Netherlands.
Trends Cancer. 2022 Dec;8(12):980-987. doi: 10.1016/j.trecan.2022.07.007. Epub 2022 Aug 11.
Immune effector cells, including cytotoxic T cells (CTLs), induce apoptosis and eliminate target cells by direct cell-cell contacts. In vivo, CTLs fail to efficiently kill solid tumor cells by individual contacts but rely upon multihit interactions by many CTLs (swarming). Recent evidence has indicated that multihit interactions by CTLs induce a series of sublethal damage events in target cells, including perforin-mediated membrane damage, induction of reactive oxygen species (ROS), nuclear envelope rupture, and DNA damage. Individual damage can be repaired, but when induced in rapid sequence, sublethal damage can accumulate and induce target cell death. Here, we summarize the sublethal damage and additive cytotoxicity concepts for CTL-induced and other cell stresses and discuss the implications for improving immunotherapy and multitargeted anticancer therapies.
免疫效应细胞，包括细胞毒性 T 细胞（CTL），通过直接的细胞-细胞接触诱导细胞凋亡并消除靶细胞。在体内，CTL 通过单个接触无法有效地杀死实体肿瘤细胞，但依赖于许多 CTL 的多击相互作用（群集）。最近的证据表明，CTL 的多击相互作用会在靶细胞中诱导一系列亚致死性损伤事件，包括穿孔素介导的膜损伤、活性氧（ROS）的诱导、核膜破裂和 DNA 损伤。单个损伤可以被修复，但是当以快速序列诱导时，亚致死性损伤可以累积并诱导靶细胞死亡。在这里，我们总结了 CTL 诱导的和其他细胞应激的亚致死性损伤和相加细胞毒性概念，并讨论了改善免疫疗法和多靶点抗癌疗法的意义。
