Tserunyan Vardges, Finley Stacey D
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
R Soc Open Sci. 2022 Aug 24;9(8):220137. doi: 10.1098/rsos.220137. eCollection 2022 Aug.
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 typically includes costimulatory domains, which enhance the T-cell response upon antigen encounter. However, it is not fully known how those co-stimulatory domains influence cell activation in the presence of biological variability. In this work, we used mathematical modelling to elucidate how the inclusion of one such costimulatory molecule, CD28, impacts the response of a population of CAR T cells under different sources of variability. Particularly, we demonstrate that CD28-bearing CARs mediate a faster and more consistent population response under both target antigen variability and kinetic rate variability. Next, we identify kinetic parameters that have the most impact on cell response time. Finally, based on our findings, we propose that enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase can result in drastically reduced and more consistent response times among heterogeneous CAR T-cell populations.
近几十年来，嵌合抗原受体（CARs）已成功用于生成能够识别和消除癌细胞的工程化T细胞。CARs的结构通常包括共刺激结构域，其在遇到抗原时增强T细胞反应。然而，在存在生物学变异性的情况下，这些共刺激结构域如何影响细胞活化尚不完全清楚。在这项工作中，我们使用数学建模来阐明包含一种这样的共刺激分子CD28如何在不同变异性来源下影响CAR T细胞群体的反应。特别地，我们证明在靶抗原变异性和动力学速率变异性下，携带CD28的CARs介导更快且更一致的群体反应。接下来，我们确定对细胞反应时间影响最大的动力学参数。最后，基于我们的发现，我们提出增强淋巴细胞特异性蛋白酪氨酸激酶的催化活性可导致异质CAR T细胞群体中的反应时间大幅缩短且更加一致。
