Abstract
Natural killer (NK) cells engage target cells via the immunological synapse, where inhibitory and activating signals determine whether NK cell cytotoxicity is suppressed or activated. We report that cancer cells can rapidly remodel their actin cytoskeleton upon NK cell engagement, leading to F-actin accumulation at the synapse. This process inhibits NK cell activation as indicated by impaired MTOC and lytic granule polarization. Exploring the underlying mechanism, we found that actin remodelling 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 restored 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 a novel immune evasion strategy in which cancer cells impair NK cell activation by altering synaptic signalling through actin cytoskeleton-driven recruitment of inhibitory signals to the immunological synapse.
Full text
1,230 characters
· extracted from
oa-doi-fallback
· click to expand
Abstract
Natural killer (NK) cells engage target cells via the immunological synapse, where inhibitory and activating signals determine whether NK cell cytotoxicity is suppressed or activated. We report that cancer cells can rapidly remodel their actin cytoskeleton upon NK cell engagement, leading to F-actin accumulation at the synapse. This process inhibits NK cell activation as indicated by impaired MTOC and lytic granule polarization. Exploring the underlying mechanism, we found that actin remodelling 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 restored 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 a novel immune evasion strategy in which cancer cells impair NK cell activation by altering synaptic signalling through actin cytoskeleton-driven recruitment of inhibitory signals to the immunological synapse.
Competing Interest Statement
The authors have declared no competing interest.
Text is read by the "Ask this paper" AI Q&A widget below.
Extraction quality varies by source — PMC NXML preserves structure
cleanly, OA-HTML may include some navigation residue, and OA-PDF can
have broken hyphenation. The publisher copy
(via DOI)
is the canonical version.