Agent-based Modeling of Tumor and Immune System Interactions in Combinational Therapy with Low-dose 5-fluorouracil and Dendritic Cell Vaccine in Melanoma B16F10
-
Sarah Rahbar
,
Sajad Shafiekhani
,
Armin Allahverdi
,
Arezoo Jamali
,
Nasim Kheshtchin
,
Maryam Ajami
,
Zahra Mirsanei
,
Sima Habibi
,
Bahador Makkiabadi
,
Jamshid Hadjati
,
Amir Homayoun Jafari
Abstract
This study is designed to present an agent-based model (ABM) to simulate the interactions between tumor cells and the immune system in the melanoma model. The Myeloid-derived Suppressor Cells (MDSCs) and dendritic cells (DCs) are considered in this model as immunosuppressive and antigen-presenting agents respectively.
The animal experiment was performed on 68 B16F10 melanoma tumor-bearing C57BL/6 female mice to collect dynamic data for ABM implementation and validation. Animals were divided into 4 groups; group 1 was control (no treatment) while groups 2 and 3 were treated with DC vaccine and low-dose 5- fluorouracil (5-FU) respectively and group 4 was treated with both DC Vaccine and low-dose of 5-FU. The tumor growth rate, number of MDSC, and presence of CD8+/CD107a+ T cells in the tumor microenvironment were evaluated in each group. Firstly, the tumor cells, the effector immune cells, DCs, and the MDSCs have been considered as the agents of the ABM model and their interaction methods have been extracted from the literature and implemented in the model. Then, the model parameters were estimated by the dynamic data collected from animal experiments.
To validate the ABM model, the simulation results were compared with the real data. The results show that the dynamics of the model agents can mimic the relations among considered immune system components to an emergent outcome compatible with real data. The simplicity of the proposed model can help to understand the results of the combinational therapy and make this model a useful tool for studying different scenarios and assessing the combinational results.
Determining the role of each component helps to find critical times during tumor progression and change the tumor and immune system balance in favor of the immune system.
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8. Namdar A, Mirzaei HR, Jadidi-Niaragh F, Ashourpour M, Ajami M, Hadjati J, Rezaei A. Multiple Low Doses of 5-Fluorouracil Diminishes Immunosuppression by Myeloid Derived Suppressor Cells in Murine Melanoma Model. Iran J Immunol. 2015;12(3):176-87.
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11. Kuznetsov VA, Makalkin IA, Taylor MA, Perelson AS. Nonlinear dynamics of immunogenic tumors: parameter estimation and global bifurcation analysis. Bull Math Biol. 1994;56(2):295-321.
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15. Figueredo GP, Joshi TV, Osborne JM, Byrne HM, Owen MR. On-lattice agent-based simulation of populations of cells within the open-source Chaste framework. Interface Focus. 2013;3(2):20120081.
16. Figueredo GP, Siebers PO, Owen MR, Reps J, Aickelin U. Comparing stochastic differential equations and agent-based modelling and simulation for early-stage cancer. PLoS One. 2014;9(4):e95150.
17. Allahverdy A, Rahbar S, Mirzaei HR, Ajami M, Namdar A, Habibi S, Hadjati J, Jafari AH. Extracting Mutual Interaction Rules Using Fuzzy Structured Agent-based Model of Tumor-Immune System Interactions. J Biomed Phys Eng. 2021;11(1):61-72.
18. Inaba K, Inaba M, Naito M, Steinman RM. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med. 1993 Aug 1;178(2):479-88.
19. de Camargo MR, Kaneno R, de Camargo MR, Vannini P, Kaneno R, Ostrand-Rosemberg S. Low Dose Of 5-Fluorouracil Combined with A Dendritic Cell Vaccine Delays the Growth of Colorectal Cancer in Mice. Biomed J Sci Tech Res. 2020;29(4):22583-7.
20. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C, Ghiringhelli F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052-61.
21. Lee TH, Cho YH, Lee MG. Larger numbers of immature dendritic cells augment an anti-tumor effect against established murine melanoma cells. Biotechnol Lett. 2007;29(3):351-7.
22. Zhou J. Advances and prospects in cancer immunotherapy. New J. Sci. 2014;2014.
23. Stewart TJ, Smyth MJ. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev. 2011;30(1):125-40.
24. Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother. 2012;61(2):283-288.
25. Ménard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother. 2008;57(11):1579-87. doi: 10
26. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59-73.
27. Namdar A, Mirzaei HR, Hafezi M, Khosravianfar N, Kheshtchin N, Mirzaei R, Hadjati J, Rezaei A. Low Noncytotoxic Concentrations of 5-Fluorouracil Have No Adverse Effects on Maturation and Function of Bone Marrow-Derived Dendritic Cells in vitro: A Potentially Safe Adjuvant for Dendritic Cell-Based Cancer Therapy. Int Arch Allergy Immunol. 2015;168(2):122-30.
28. de Camargo MR, Kaneno R, de Camargo MR, Vannini P, Kaneno R, Ostrand-Rosemberg S. Low Dose Of 5-Fluorouracil Combined with A Dendritic Cell Vaccine Delays the Growth of Colorectal Cancer in Mice. Biomed J Sci Tech Res. 2020;29(4):22583-7.
29. Khosravianfar N, Hadjati J, Namdar A, Boghozian R, Hafezi M, Ashourpour M, Kheshtchin N, Banitalebi M, Mirzaei R, Razavi SA. Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cell-based Vaccine Function and Improved Immunity in Tumor Mice. Iran J Allergy Asthma Immunol. 2018;17(1):47-55.
30. Qomlaqi M, Bahrami F, Ajami M, Hajati J. An extended mathematical model of tumor growth and its interaction with the immune system, to be used for developing an optimized immunotherapy treatment protocol. Math Biosci. 2017;292(15):1-9.
31. Depillis L, Gallegos A, Radunskaya A. A model of dendritic cell therapy for melanoma. Front Oncol. 2013 Mar 19;3:56.
32. Mirsanei Z, Habibi S, Kheshtchin N, Mirzaei R, Arab S, Zand B, Jadidi-Niaragh F, Safvati A, Sharif-Paghaleh E, Arabameri A, Asemani D, Hajati J. Optimized Dose of Dendritic Cell-based Vaccination in Experimental Model of Tumor Using Artificial Neural Network. Iran J Allergy Asthma Immunol. 2020;19(2):172-182.
33. Allahverdy A, Moghaddam AK, Rahbar S, Shafiekhani S, Mirzaie HR, Amanpour S, Etemadi Y, Hadjati J, Jafari AH. An Agent-based Model for Investigating the Effect of Myeloid-Derived Suppressor Cells and its Depletion on Tumor Immune Surveillance. J Med Signals Sens. 20;9(1):15-23.
34. Shafiekhani S, Jafari AH, Jafarzadeh L, Gheibi N. In Silico Assessment of 5-FU Therapy via A Mathematical Model with Fuzzy Uncertain Parameters. 2020, manuscript accepted for publication in BMC Cancer.
2. Seung LP, Rowley DA, Dubey P, Schreiber H. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci U S A. 1995;92(14):6254-8.
3. Young MR, Newby M, Wepsic HT. Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res. 1987;47(1):100-5.
4. Abedi-Valugerdi M, Zheng W, Benkessou F, Zhao Y, Hassan M. Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice. Int Immunopharmacol. 2017;47(4):173-181.
5. Umansky V, Sevko A. Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron. 2013;6(2):169-77.
6. Umansky V, Sevko A, Gebhardt C, Utikal J. Myeloid-derived suppressor cells in malignant melanoma. J Dtsch Dermatol Ges. 2014;12(11):1021-7.
7. Shou D, Wen L, Song Z, Yin J, Sun Q, Gong W. Suppressive role of myeloid-derived suppressor cells (MDSCs) in the microenvironment of breast cancer and targeted immunotherapies. Oncotarget. 2016 Sep 27;7(39):64505-64511.
8. Namdar A, Mirzaei HR, Jadidi-Niaragh F, Ashourpour M, Ajami M, Hadjati J, Rezaei A. Multiple Low Doses of 5-Fluorouracil Diminishes Immunosuppression by Myeloid Derived Suppressor Cells in Murine Melanoma Model. Iran J Immunol. 2015;12(3):176-87.
9. Lala PK, Patt HM. Cytokinetic analysis of tumor growth. Proc Natl Acad Sci U S A. 1966;56(6):1735-42.
10. Spratt JS, Meyer JS, Spratt JA. Rates of growth of human neoplasms: Part II. J Surg Oncol. 1996 Jan;61(1):68-83.
11. Kuznetsov VA, Makalkin IA, Taylor MA, Perelson AS. Nonlinear dynamics of immunogenic tumors: parameter estimation and global bifurcation analysis. Bull Math Biol. 1994;56(2):295-321.
12. Kirschner D, Panetta JC. Modeling immunotherapy of the tumor-immune interaction. J Math Biol. 1998 Sep;37(3):235-52.
13. Arciero J, Jackson T, Kirschner D. A mathematical model of tumor-immune evasion and siRNA treatment. Discrete and Continuous Dynamical Systems Series B. 2004;4(1):39-58.
14. Byrne HM, Alarcon T, Owen MR, Webb SD, Maini PK. Modelling aspects of cancer dynamics: a review. Philos Trans A Math Phys Eng Sci. 2006;364(1843):1563-78.
15. Figueredo GP, Joshi TV, Osborne JM, Byrne HM, Owen MR. On-lattice agent-based simulation of populations of cells within the open-source Chaste framework. Interface Focus. 2013;3(2):20120081.
16. Figueredo GP, Siebers PO, Owen MR, Reps J, Aickelin U. Comparing stochastic differential equations and agent-based modelling and simulation for early-stage cancer. PLoS One. 2014;9(4):e95150.
17. Allahverdy A, Rahbar S, Mirzaei HR, Ajami M, Namdar A, Habibi S, Hadjati J, Jafari AH. Extracting Mutual Interaction Rules Using Fuzzy Structured Agent-based Model of Tumor-Immune System Interactions. J Biomed Phys Eng. 2021;11(1):61-72.
18. Inaba K, Inaba M, Naito M, Steinman RM. Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med. 1993 Aug 1;178(2):479-88.
19. de Camargo MR, Kaneno R, de Camargo MR, Vannini P, Kaneno R, Ostrand-Rosemberg S. Low Dose Of 5-Fluorouracil Combined with A Dendritic Cell Vaccine Delays the Growth of Colorectal Cancer in Mice. Biomed J Sci Tech Res. 2020;29(4):22583-7.
20. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C, Ghiringhelli F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052-61.
21. Lee TH, Cho YH, Lee MG. Larger numbers of immature dendritic cells augment an anti-tumor effect against established murine melanoma cells. Biotechnol Lett. 2007;29(3):351-7.
22. Zhou J. Advances and prospects in cancer immunotherapy. New J. Sci. 2014;2014.
23. Stewart TJ, Smyth MJ. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev. 2011;30(1):125-40.
24. Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother. 2012;61(2):283-288.
25. Ménard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother. 2008;57(11):1579-87. doi: 10
26. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8(1):59-73.
27. Namdar A, Mirzaei HR, Hafezi M, Khosravianfar N, Kheshtchin N, Mirzaei R, Hadjati J, Rezaei A. Low Noncytotoxic Concentrations of 5-Fluorouracil Have No Adverse Effects on Maturation and Function of Bone Marrow-Derived Dendritic Cells in vitro: A Potentially Safe Adjuvant for Dendritic Cell-Based Cancer Therapy. Int Arch Allergy Immunol. 2015;168(2):122-30.
28. de Camargo MR, Kaneno R, de Camargo MR, Vannini P, Kaneno R, Ostrand-Rosemberg S. Low Dose Of 5-Fluorouracil Combined with A Dendritic Cell Vaccine Delays the Growth of Colorectal Cancer in Mice. Biomed J Sci Tech Res. 2020;29(4):22583-7.
29. Khosravianfar N, Hadjati J, Namdar A, Boghozian R, Hafezi M, Ashourpour M, Kheshtchin N, Banitalebi M, Mirzaei R, Razavi SA. Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cell-based Vaccine Function and Improved Immunity in Tumor Mice. Iran J Allergy Asthma Immunol. 2018;17(1):47-55.
30. Qomlaqi M, Bahrami F, Ajami M, Hajati J. An extended mathematical model of tumor growth and its interaction with the immune system, to be used for developing an optimized immunotherapy treatment protocol. Math Biosci. 2017;292(15):1-9.
31. Depillis L, Gallegos A, Radunskaya A. A model of dendritic cell therapy for melanoma. Front Oncol. 2013 Mar 19;3:56.
32. Mirsanei Z, Habibi S, Kheshtchin N, Mirzaei R, Arab S, Zand B, Jadidi-Niaragh F, Safvati A, Sharif-Paghaleh E, Arabameri A, Asemani D, Hajati J. Optimized Dose of Dendritic Cell-based Vaccination in Experimental Model of Tumor Using Artificial Neural Network. Iran J Allergy Asthma Immunol. 2020;19(2):172-182.
33. Allahverdy A, Moghaddam AK, Rahbar S, Shafiekhani S, Mirzaie HR, Amanpour S, Etemadi Y, Hadjati J, Jafari AH. An Agent-based Model for Investigating the Effect of Myeloid-Derived Suppressor Cells and its Depletion on Tumor Immune Surveillance. J Med Signals Sens. 20;9(1):15-23.
34. Shafiekhani S, Jafari AH, Jafarzadeh L, Gheibi N. In Silico Assessment of 5-FU Therapy via A Mathematical Model with Fuzzy Uncertain Parameters. 2020, manuscript accepted for publication in BMC Cancer.
| Files | ||
| Issue | Vol 21 No 2 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i2.9223 | |
| Keywords | ||
| Fluorouracil Melanoma Myeloid-derived suppressor cells Tumor microenvironment | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Rahbar S, Shafiekhani S, Allahverdi A, Jamali A, Kheshtchin N, Ajami M, Mirsanei Z, Habibi S, Makkiabadi B, Hadjati J, Jafari A. Agent-based Modeling of Tumor and Immune System Interactions in Combinational Therapy with Low-dose 5-fluorouracil and Dendritic Cell Vaccine in Melanoma B16F10. Iran J Allergy Asthma Immunol. 2022;21(2):151-166.
