Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells
Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, the...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2567 |
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| author | Richard J. Beck Bettina Weigelin Joost B. Beltman |
| author_facet | Richard J. Beck Bettina Weigelin Joost B. Beltman |
| author_sort | Richard J. Beck |
| collection | DOAJ |
| description | Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. Moreover, we found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation. |
| first_indexed | 2024-03-10T11:06:52Z |
| format | Article |
| id | doaj.art-ebf6c54c04c84858886c7d0fde7df5cd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:06:52Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ebf6c54c04c84858886c7d0fde7df5cd2023-11-21T21:07:06ZengMDPI AGCancers2072-66942021-05-011311256710.3390/cancers13112567Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour CellsRichard J. Beck0Bettina Weigelin1Joost B. Beltman2Leiden Academic Centre for Drug Research, Division of Drug Discovery and Safety, Leiden University, 2333 CC Leiden, The NetherlandsDepartment of Preclinical Imaging and Radiopharmacy, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyLeiden Academic Centre for Drug Research, Division of Drug Discovery and Safety, Leiden University, 2333 CC Leiden, The NetherlandsSeveral immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of CTLs and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation. Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities. We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. Moreover, we found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation.https://www.mdpi.com/2072-6694/13/11/2567mathematical modellingordinary differential equationscytotoxic T lymphocytesT cellstumourimmunotherapy |
| spellingShingle | Richard J. Beck Bettina Weigelin Joost B. Beltman Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells Cancers mathematical modelling ordinary differential equations cytotoxic T lymphocytes T cells tumour immunotherapy |
| title | Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells |
| title_full | Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells |
| title_fullStr | Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells |
| title_full_unstemmed | Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells |
| title_short | Mathematical Modelling Based on In Vivo Imaging Suggests CD137-Stimulated Cytotoxic T Lymphocytes Exert Superior Tumour Control Due to an Enhanced Antimitotic Effect on Tumour Cells |
| title_sort | mathematical modelling based on in vivo imaging suggests cd137 stimulated cytotoxic t lymphocytes exert superior tumour control due to an enhanced antimitotic effect on tumour cells |
| topic | mathematical modelling ordinary differential equations cytotoxic T lymphocytes T cells tumour immunotherapy |
| url | https://www.mdpi.com/2072-6694/13/11/2567 |
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