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Rac1/ROCK-driven membrane dynamics promote natural killer cell cytotoxicity via granzyme-induced necroptosis
Yanting Zhu1, Jun Xie1, Jue Shi2
1Center for Quantitative Systems Biology, Department of Physics and Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong, China.
Background:
Natural killer (NK) cells play an important role in cancer immunosurveillance and therapy. However, the target selectivity of NK cell activity is still poorly understood.
Results:
Here, we used live-cell reporters to unravel differential epithelial cancer target killing by primary human NK cells. We found highly variable fractions of killing by distinct NK cell cytotoxic modes that were not determined by NK ligand expression. Rather, epithelial plasma membrane dynamics driven by ROCK-mediated blebs and/or Rac1-mediated lamellipodia promoted necrotic mode in preference to the apoptotic mode of killing. Inhibition of granzyme B and key necroptosis regulators RIP1, RIP3, and MLKL significantly attenuated the necrotic killing, revealing a novel NK cell cytotoxic pathway by granzyme-induced necroptosis that conferred target selectivity.
Conclusions:
Our results not only elucidate a new NK cell effector mechanism but also suggest that tissue microenvironment and oncogenic signaling pathways that promote membrane dynamics, e.g., Rac1 and Rho/ROCK, could be exploited to enhance proinflammatory NK cell killing.
Insights
Natural killer (NK) cells exhibit variable cancer cell killing. Researchers discovered that epithelial cell membrane dynamics, not NK cell ligands, dictate NK cell cytotoxic modes, revealing a novel granzyme-induced necroptosis pathway for enhanced cancer therapy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for cancer immunosurveillance and immunotherapy.
- The precise mechanisms governing NK cell target selectivity remain incompletely understood.
Purpose of the Study:
- To investigate the differential killing of epithelial cancer targets by primary human NK cells.
- To elucidate the role of epithelial cell membrane dynamics in NK cell-mediated cytotoxicity.
Main Methods:
- Utilized live-cell reporters to monitor NK cell interactions with epithelial cancer targets.
- Assessed the impact of epithelial plasma membrane dynamics (ROCK-mediated blebs, Rac1-mediated lamellipodia) on NK cell killing modes.
- Investigated the involvement of granzyme B and necroptosis regulators (RIP1, RIP3, MLKL) in NK cell cytotoxicity.
Main Results:
- NK cell killing efficiency varied significantly and was not solely dependent on NK ligand expression on target cells.
- Epithelial cell membrane dynamics, specifically blebs and lamellipodia, preferentially promoted a necrotic killing mode over an apoptotic mode.
- Inhibition of granzyme B and necroptosis regulators attenuated necrotic killing, indicating a novel granzyme-induced necroptosis pathway.
Conclusions:
- Identified a novel NK cell effector mechanism involving granzyme-induced necroptosis, contributing to target selectivity.
- Demonstrated that epithelial cell membrane dynamics play a critical role in dictating NK cell cytotoxic outcomes.
- Suggests that targeting tissue microenvironment and oncogenic signaling pathways (e.g., Rac1, Rho/ROCK) could enhance NK cell-mediated cancer killing.
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