Cancer cells suppress NK cell activity by actin-driven polarization of inhibitory ligands to the immunological synapse

• 成果类型: Article
• 署名作者: Hoffmann, Celine; Filali, Liza; Wurzer, Hannah; Fernandes, Diogo Pereira; Mgrditchian, Takouhie; Huang, Wanxin; Moreau, Flora; Krecke, Max; Thomas, Clement
• 署名单位: Luxembourg Institute of Health; Luxembourg Institute of Health; University of Luxembourg; Eberhard Karls University of Tubingen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12427
• DOI: 10.1073/pnas.2503259122
• 发表日期: 2025-08-12
• 关键词: dendritic cells; activation; cytotoxicity; receptors; responses; requires; signals

摘要

Natural killer (NK) cells engage target cells via the immunological synapse (IS), where inhibitory and activating signals determine whether NK cell cytotoxicity is suppressed or activated. We previously reported that cancer cells can rapidly remodel their actin cytoskeleton upon NK cell engagement, leading to F-actin accumulation at the synapse. Here, we show that this process inhibits NK cell activation as indicated by impaired MTOC and lytic granule polarization. Exploring the underlying mechanism, we demonstrate that actin remodeling drives the recruitment of inhibitory ligands, such as HLA-A,-B, and-C, to the synapse. Disrupting HLA interaction with their cognate inhibitory receptors KIRs restores NK cell activation. Using NK cells expressing inhibitory KIR receptors, matched or unmatched to HLA molecules on cancer cells, we show that synaptic F-actin accumulation and matching KIR-HLA interactions jointly suppress NK cell cytotoxicity. Our findings reveal an immune evasion strategy in which cancer cells impair NK cell activation by altering synaptic signaling through actin cytoskeleton-driven recruitment of inhibitory signals to the IS. Significance Our findings provide insights into previously uncharacterized dynamics at the cancer cell-cytotoxic lymphocyte interface, uncovering a critical mechanism by which actin cytoskeleton remodeling at the cancer cell side promotes resistance to natural killer (NK) cell-mediated cytotoxicity. We demonstrate that actin-driven polarization of NK cell inhibitory ligands to the cancer cell side of the immunological synapse amplifies inhibitory signaling, thereby suppressing NK cell lytic activity. These findings shed light on previously uncharacterized molecular strategies employed by cancer cells to evade NK cell-mediated cytotoxicity and may have important implications for advancing our understanding of cancer immune evasion and developing more effective immunotherapeutic interventions.