Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Immunology Research Group, University of Calgary, Calgary, Alberta, Canada.
Cell Rep. 2018 Jun 26;23(13):3946-3959.e6. doi: 10.1016/j.celrep.2018.05.082.
Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPα checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPα interactions.
治疗性抗体通过抗体依赖性细胞毒性（ADCC）杀伤癌细胞，ADCC 可由多种表达 Fc 受体的免疫细胞介导，包括中性粒细胞。然而，中性粒细胞杀伤抗体包被的癌细胞的机制尚未确定。本研究中，我们证明中性粒细胞可以通过抗体介导的细胞胞饮作用杀伤癌细胞，这涉及中性粒细胞的细胞胞饮作用。与此密切相关的是，癌细胞质膜被主动破坏，导致癌细胞发生裂解（即坏死）死亡。此外，CD47-SIRPα 检查点阻断可增强中性粒细胞对抗体包被的癌细胞的这种杀伤作用。综上所述，这些发现表明，中性粒细胞通过一种称为 trogoptosis 的细胞毒性机制发挥对癌细胞的 ADCC 作用，通过靶向 CD47-SIRPα 相互作用可进一步增强这种作用。
