Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a mo...
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MDPI AG
2022-11-01
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author | Fateme Safaeifard Bahram Goliaei Amir R. Aref Mohammad-Hadi Foroughmand-Araabi Sama Goliaei Jochen Lorch Russell W. Jenkins David A. Barbie Seyed Peyman Shariatpanahi Curzio Rüegg |
author_facet | Fateme Safaeifard Bahram Goliaei Amir R. Aref Mohammad-Hadi Foroughmand-Araabi Sama Goliaei Jochen Lorch Russell W. Jenkins David A. Barbie Seyed Peyman Shariatpanahi Curzio Rüegg |
author_sort | Fateme Safaeifard |
collection | DOAJ |
description | Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a more comprehensive insight into the coordinated function of these immune regulators. Mathematical modeling can be used to elucidate nonlinear tumor–immune interactions and highlight the underlying mechanisms to tackle the problem. Here, we investigated and statistically characterized the dynamics of T-cell migration as a measure of the functional response to these pathways. We used a previously developed three-dimensional organotypic culture of patient-derived tumor spheroids treated with anti-CTLA-4 and anti-PD-1 antibodies for this purpose. Experiment-based dynamical modeling revealed the delayed kinetics of PD-1 activation, which originates from the distinct characteristics of PD-1 and CTLA-4 regulation, and followed through with the modification of their contributions to immune modulation. The simulation results show good agreement with the tumor cell reduction and active immune cell count in each experiment. Our findings demonstrate that while PD-1 activation provokes a more exhaustive intracellular cascade within a mature tumor environment, the time-delayed kinetics of PD-1 activation outweighs its preeminence at the individual cell level and consequently confers a functional dominance to the CTLA-4 checkpoint. The proposed model explains the distinct immunostimulatory pattern of PD-1 and CTLA-4 blockade based on mechanisms involved in the regulation of their expression and may be useful for planning effective treatment schemes targeting PD-1 and CTLA-4 functions. |
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language | English |
last_indexed | 2024-03-09T18:25:52Z |
publishDate | 2022-11-01 |
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series | Cells |
spelling | doaj.art-e42517ea3a8c4fdbbbf3282487873c9e2023-11-24T07:57:00ZengMDPI AGCells2073-44092022-11-011122353410.3390/cells11223534Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint BlockadeFateme Safaeifard0Bahram Goliaei1Amir R. Aref2Mohammad-Hadi Foroughmand-Araabi3Sama Goliaei4Jochen Lorch5Russell W. Jenkins6David A. Barbie7Seyed Peyman Shariatpanahi8Curzio Rüegg9Laboratory of Biophysics and Molecular Biology, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 1417614411, IranLaboratory of Biophysics and Molecular Biology, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 1417614411, IranDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Mathematical Sciences, Sharif University of Technology, Tehran P.O. Box 11155-9415, IranFaculty of New Sciences & Technologies, University of Tehran, Tehran 1439957131, IranDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USAMassGeneral Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USALaboratory of Biophysics and Molecular Biology, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 1417614411, IranLaboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology, and Immunology, Faculty of Sciences and Medicine, University of Fribourg, 1700 Fribourg, SwitzerlandCytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a more comprehensive insight into the coordinated function of these immune regulators. Mathematical modeling can be used to elucidate nonlinear tumor–immune interactions and highlight the underlying mechanisms to tackle the problem. Here, we investigated and statistically characterized the dynamics of T-cell migration as a measure of the functional response to these pathways. We used a previously developed three-dimensional organotypic culture of patient-derived tumor spheroids treated with anti-CTLA-4 and anti-PD-1 antibodies for this purpose. Experiment-based dynamical modeling revealed the delayed kinetics of PD-1 activation, which originates from the distinct characteristics of PD-1 and CTLA-4 regulation, and followed through with the modification of their contributions to immune modulation. The simulation results show good agreement with the tumor cell reduction and active immune cell count in each experiment. Our findings demonstrate that while PD-1 activation provokes a more exhaustive intracellular cascade within a mature tumor environment, the time-delayed kinetics of PD-1 activation outweighs its preeminence at the individual cell level and consequently confers a functional dominance to the CTLA-4 checkpoint. The proposed model explains the distinct immunostimulatory pattern of PD-1 and CTLA-4 blockade based on mechanisms involved in the regulation of their expression and may be useful for planning effective treatment schemes targeting PD-1 and CTLA-4 functions.https://www.mdpi.com/2073-4409/11/22/3534organotypic tumor cultureimmune checkpoint blockadeT-cell migrationheterogeneous random walkstumor–immune interactiondelayed dynamics |
spellingShingle | Fateme Safaeifard Bahram Goliaei Amir R. Aref Mohammad-Hadi Foroughmand-Araabi Sama Goliaei Jochen Lorch Russell W. Jenkins David A. Barbie Seyed Peyman Shariatpanahi Curzio Rüegg Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade Cells organotypic tumor culture immune checkpoint blockade T-cell migration heterogeneous random walks tumor–immune interaction delayed dynamics |
title | Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade |
title_full | Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade |
title_fullStr | Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade |
title_full_unstemmed | Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade |
title_short | Distinct Dynamics of Migratory Response to PD-1 and CTLA-4 Blockade Reveals New Mechanistic Insights for Potential T-Cell Reinvigoration following Immune Checkpoint Blockade |
title_sort | distinct dynamics of migratory response to pd 1 and ctla 4 blockade reveals new mechanistic insights for potential t cell reinvigoration following immune checkpoint blockade |
topic | organotypic tumor culture immune checkpoint blockade T-cell migration heterogeneous random walks tumor–immune interaction delayed dynamics |
url | https://www.mdpi.com/2073-4409/11/22/3534 |
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