RT Journal Article
SR Electronic
T1 Modeling predicts differences in CAR T cell signaling due to biological variability
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.14.476364
DO 10.1101/2022.01.14.476364
A1 Vardges Tserunyan
A1 Stacey D. Finley
YR 2022
UL http://biorxiv.org/content/early/2022/06/21/2022.01.14.476364.abstract
AB In recent decades, chimeric antigen receptors (CARs) have been successfully used to generate engineered T cells capable of recognizing and eliminating cancer cells. The structure of CARs frequently includes costimulatory domains, which enhance the T cell response upon antigen encounter. However, it is not fully known how the CAR co-stimulatory domains influence T cell activation in the presence of biological variability. In this work, we used mathematical modeling to elucidate how the inclusion of one such co-stimulatory molecule, CD28, impacts the response of a population of engineered T cells under different sources of variability. Particularly, our simulations demonstrate that CD28-bearing CARs mediate a faster and more consistent population response under both target antigen variability and kinetic rate variability. We identify kinetic parameters that have the most impact on mediating cell activation. Finally, based on our findings, we propose that enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase (LCK) can result in drastically reduced and more consistent response times among heterogeneous CAR T cell populations.Competing Interest StatementThe authors have declared no competing interest.