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bioRxiv · 10.1101/2023.06.09.544433

Information-theoretic analysis of a model of CAR-4-1BB-mediated NFκB activation

Tserunyan, V.·Finley, S. D.
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Abstract

Systems biology utilizes computational approaches to examine an array of biological processes, such as cell signaling, metabolomics and pharmacology. This includes mathematical modeling of CAR T cells, a modality of cancer therapy by which genetically engineered immune cells recognize and combat a cancerous target. While successful against hematologic malignancies, CAR T cells have shown limited success against other cancer types. Thus, more research is needed to understand their mechanisms of action and leverage their full potential. In our work, we set out to apply information theory on a mathematical model of cell signaling of CAR-mediated activation following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NF{kappa}B signal transduction. Next, we evaluated the pathways ability to distinguish contrasting "low" and "high" antigen concentration levels, depending on the amount of intrinsic noise. Finally, we assessed the fidelity by which NF{kappa}B activation reflects the encountered antigen concentration, depending on the prevalence of antigen-positive targets in tumor population. We found that in most scenarios, fold change in the nuclear concentration of NF{kappa}B carries a higher channel capacity for the pathway than NF{kappa}Bs absolute response. Additionally, we found that most errors in transducing the antigen signal through the pathway skew towards underestimating the concentration of encountered antigen. Finally, we found that disabling IKK{beta} deactivation could increase signaling fidelity against targets with antigen-negative cells. Our information-theoretic analysis of signal transduction can provide novel perspectives on biological signaling, as well as enable a more informed path to cell engineering.

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Tserunyan, V., Finley, S. D.. 2023-06-10. Information-theoretic analysis of a model of CAR-4-1BB-mediated NFκB activation. https://doi.org/10.1101/2023.06.09.544433

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