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Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation
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 c...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691998/ https://www.ncbi.nlm.nih.gov/pubmed/38038772 http://dx.doi.org/10.1007/s11538-023-01232-6 |
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author | Tserunyan, Vardges Finley, Stacey |
author_facet | Tserunyan, Vardges Finley, Stacey |
author_sort | Tserunyan, Vardges |
collection | PubMed |
description | 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 NFκB signaling initiated by the CAR following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NFκB signal transduction. Next, we evaluated the pathway’s ability to distinguish contrasting “low” and “high” antigen concentration levels, depending on the amount of variability in protein concentrations. Finally, we assessed the fidelity by which NFκB 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 NFκB carries a higher channel capacity for the pathway than NFκB’s 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 IKKβ 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.Kindly check and confirm whether the corresponding affiliation is correctly identified.this is correct SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11538-023-01232-6. |
format | Online Article Text |
id | pubmed-10691998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-106919982023-12-03 Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation Tserunyan, Vardges Finley, Stacey Bull Math Biol Original Article 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 NFκB signaling initiated by the CAR following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NFκB signal transduction. Next, we evaluated the pathway’s ability to distinguish contrasting “low” and “high” antigen concentration levels, depending on the amount of variability in protein concentrations. Finally, we assessed the fidelity by which NFκB 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 NFκB carries a higher channel capacity for the pathway than NFκB’s 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 IKKβ 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.Kindly check and confirm whether the corresponding affiliation is correctly identified.this is correct SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11538-023-01232-6. Springer US 2023-12-01 2024 /pmc/articles/PMC10691998/ /pubmed/38038772 http://dx.doi.org/10.1007/s11538-023-01232-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Tserunyan, Vardges Finley, Stacey Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title | Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title_full | Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title_fullStr | Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title_full_unstemmed | Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title_short | Information-Theoretic Analysis of a Model of CAR-4-1BB-Mediated NFκB Activation |
title_sort | information-theoretic analysis of a model of car-4-1bb-mediated nfκb activation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691998/ https://www.ncbi.nlm.nih.gov/pubmed/38038772 http://dx.doi.org/10.1007/s11538-023-01232-6 |
work_keys_str_mv | AT tserunyanvardges informationtheoreticanalysisofamodelofcar41bbmediatednfkbactivation AT finleystacey informationtheoreticanalysisofamodelofcar41bbmediatednfkbactivation |