Speaker
Description
Natural Killer (NK) cells mediate tumor cell killing through mechanisms such as granzyme–perforin release and death ligand–induced activation of the extrinsic apoptosis pathway \cite{Prager2019}. Among them, the TNF-related apoptosis-inducing ligand (TRAIL) plays a central role and has been widely explored as a therapeutic agent. However, its efficacy is consistently limited by fractional killing, whereby a subset of cells remains tolerant even at high doses\cite{roux2015fractional}. To investigate the origin of this heterogeneity, we develop a mechanistic model of the TRAIL-induced apoptosis pathway \cite{fiandaca2025drug}. By fitting the model to single-cell time resolved FRET trajectories monitoring apoptosis commitment across multiple doses, we infer latent, cell-specific protein abundances together with key kinetic parameters, recapitulating the full diversity of observed responses. These inferred parameters define a continuous state space describing each cell’s underlying biochemical configuration. By linking each trajectory to early signaling dynamics, we identify a dose-dependent decision boundary within this space that separates apoptotic from tolerant regions, indicating that cell fate is largely determined by a cell’s position in this state space at the time of treatment. Taken together, these results provide a quantitative basis for understanding heterogeneous sensitivity to TRAIL–induced apoptosis and suggests new strategies to modulate response in NK-based therapies.
Bibliography
@article{Prager2019,
title = {Target cell–induced NK cell dysfunction limits cytotoxic activity},
author = {Prager, I. and Liesche, C. and van Ooijen, H. and Urlaub, D. and Verron, Q. and Sandstr{\"o}m, N. and Fasbender, F. and Claus, M. and Eils, R. and Beaudouin, J. and Watzl, C.},
journal = {Science Immunology},
volume = {4},
number = {33},
pages = {eaav6122},
year = {2019},
doi = {10.1126/sciimmunol.aav6122}
}
@article{roux2015fractional,
title={Fractional killing arises from cell-to-cell variability in overcoming a caspase activity threshold},
author={Roux, J{\'e}r{\'e}mie and Hafner, Marc and Bandara, Samuel and Sims, Joshua J and Hudson, Hannah and Chai, Diana and Sorger, Peter K},
journal={Molecular systems biology},
volume={11},
number={5},
pages={MSB145584},
year={2015},
publisher={Springer}
}
@article{fiandaca2025drug,
title={Drug-tolerant persister cells emerge from dose-dependent positioning of a threshold surface in a continuous cell-state space of drug sensitivity},
author={Fiandaca, Giada and P{\'e}r{\'e}, Marielle and Bonhomme, Kelian and Chaves, Madalena and Roux, J{\'e}r{\'e}mie},
journal = {Under revision},
year={2025},
pages={https://hal.science/hal-05521293},
}
