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Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms

Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While molecular mechanisms of how CTLs kill their targets are relative...

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Autores principales: Majumder, Barun, Budhu, Sadna, Ganusov, Vitaly V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081166/
https://www.ncbi.nlm.nih.gov/pubmed/37034693
http://dx.doi.org/10.1101/2023.03.28.534600
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author Majumder, Barun
Budhu, Sadna
Ganusov, Vitaly V.
author_facet Majumder, Barun
Budhu, Sadna
Ganusov, Vitaly V.
author_sort Majumder, Barun
collection PubMed
description Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While molecular mechanisms of how CTLs kill their targets are relatively well understood we still lack solid quantitative understanding of the kinetics and efficiency at which CTLs kill their targets in different conditions. Collagen-fibrin gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study the cytotoxicity in vitro. Budhu et al. [1] systematically varied the number of peptide (SIINFEKL)-pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured remaining targets at different times after target and CTL co-inoculation into collagen-fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data we found that this simple “exponential-growth-mass-action-killing” model does not precisely fit the data. However, determining the best fit model proved difficult because the best performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations (E ≤ 10(7) cell/ml) the model in which tumors grow exponentially and CTLs suppress tumor’s growth non-lytically and kill tumors according to the mass-action law (SiGMA model) fitted the data with best quality. Results of power analysis suggested that longer experiments (⁓ 3 – 4 days) with 4 measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow to discriminate between alternative models. Taken together, our results suggest that interactions between tumors and CTLs in collagen-fibrin gels are more complex than a simple exponential-growth-mass-action killing model and provide support for the hypothesis that CTLs impact on tumors may go beyond direct cytotoxicity.
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spelling pubmed-100811662023-04-08 Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms Majumder, Barun Budhu, Sadna Ganusov, Vitaly V. bioRxiv Article Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While molecular mechanisms of how CTLs kill their targets are relatively well understood we still lack solid quantitative understanding of the kinetics and efficiency at which CTLs kill their targets in different conditions. Collagen-fibrin gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study the cytotoxicity in vitro. Budhu et al. [1] systematically varied the number of peptide (SIINFEKL)-pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured remaining targets at different times after target and CTL co-inoculation into collagen-fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data we found that this simple “exponential-growth-mass-action-killing” model does not precisely fit the data. However, determining the best fit model proved difficult because the best performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations (E ≤ 10(7) cell/ml) the model in which tumors grow exponentially and CTLs suppress tumor’s growth non-lytically and kill tumors according to the mass-action law (SiGMA model) fitted the data with best quality. Results of power analysis suggested that longer experiments (⁓ 3 – 4 days) with 4 measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow to discriminate between alternative models. Taken together, our results suggest that interactions between tumors and CTLs in collagen-fibrin gels are more complex than a simple exponential-growth-mass-action killing model and provide support for the hypothesis that CTLs impact on tumors may go beyond direct cytotoxicity. Cold Spring Harbor Laboratory 2023-03-29 /pmc/articles/PMC10081166/ /pubmed/37034693 http://dx.doi.org/10.1101/2023.03.28.534600 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Majumder, Barun
Budhu, Sadna
Ganusov, Vitaly V.
Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title_full Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title_fullStr Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title_full_unstemmed Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title_short Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
title_sort mathematical modeling suggests cytotoxic t lymphocytes control growth of b16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081166/
https://www.ncbi.nlm.nih.gov/pubmed/37034693
http://dx.doi.org/10.1101/2023.03.28.534600
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