Computational analysis of 4-1BB-induced NFκB signaling suggests improvements to CAR cell design.
4-1BB signaling
Adoptive cell therapy
CAR cells
Information theory
Mathematical modeling
NFκB pathway
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
26 08 2022
26 08 2022
Historique:
received:
27
04
2022
accepted:
08
07
2022
entrez:
26
8
2022
pubmed:
27
8
2022
medline:
31
8
2022
Statut:
epublish
Résumé
Chimeric antigen receptor (CAR)-expressing cells are a powerful modality of adoptive cell therapy against cancer. The potency of signaling events initiated upon antigen binding depends on the costimulatory domain within the structure of the CAR. One such costimulatory domain is 4-1BB, which affects cellular response via the NFκB pathway. However, the quantitative aspects of 4-1BB-induced NFκB signaling are not fully understood. We developed an ordinary differential equation-based mathematical model representing canonical NFκB signaling activated by CD19scFv-4-1BB. After a global sensitivity analysis on model parameters, we ran Monte Carlo simulations of cell population-wide variability in NFκB signaling and quantified the mutual information between the extracellular signal and different levels of the NFκB signal transduction pathway. In response to a wide range of antigen concentrations, the magnitude of the transient peak in NFκB nuclear concentration varies significantly, while the timing of this peak is relatively consistent. Global sensitivity analysis showed that the model is robust to variations in parameters, and thus, its quantitative predictions would remain applicable to a broad range of parameter values. The model predicts that overexpressing NEMO and disabling IKKβ deactivation can increase the mutual information between antigen levels and NFκB activation. Our modeling predictions provide actionable insights to guide CAR development. Particularly, we propose specific manipulations to the NFκB signal transduction pathway that can fine-tune the response of CD19scFv-4-1BB cells to the antigen concentrations they are likely to encounter. Video Abstract.
Sections du résumé
BACKGROUND
Chimeric antigen receptor (CAR)-expressing cells are a powerful modality of adoptive cell therapy against cancer. The potency of signaling events initiated upon antigen binding depends on the costimulatory domain within the structure of the CAR. One such costimulatory domain is 4-1BB, which affects cellular response via the NFκB pathway. However, the quantitative aspects of 4-1BB-induced NFκB signaling are not fully understood.
METHODS
We developed an ordinary differential equation-based mathematical model representing canonical NFκB signaling activated by CD19scFv-4-1BB. After a global sensitivity analysis on model parameters, we ran Monte Carlo simulations of cell population-wide variability in NFκB signaling and quantified the mutual information between the extracellular signal and different levels of the NFκB signal transduction pathway.
RESULTS
In response to a wide range of antigen concentrations, the magnitude of the transient peak in NFκB nuclear concentration varies significantly, while the timing of this peak is relatively consistent. Global sensitivity analysis showed that the model is robust to variations in parameters, and thus, its quantitative predictions would remain applicable to a broad range of parameter values. The model predicts that overexpressing NEMO and disabling IKKβ deactivation can increase the mutual information between antigen levels and NFκB activation.
CONCLUSIONS
Our modeling predictions provide actionable insights to guide CAR development. Particularly, we propose specific manipulations to the NFκB signal transduction pathway that can fine-tune the response of CD19scFv-4-1BB cells to the antigen concentrations they are likely to encounter. Video Abstract.
Identifiants
pubmed: 36028884
doi: 10.1186/s12964-022-00937-w
pii: 10.1186/s12964-022-00937-w
pmc: PMC9413922
doi:
Substances chimiques
NF-kappa B
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Tumor Necrosis Factor Receptor Superfamily, Member 9
0
Types de publication
Journal Article
Video-Audio Media
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129Informations de copyright
© 2022. The Author(s).
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