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J Theor Biol. 2018 Apr 7;442:1-10. doi: 10.1016/j.jtbi.2018.01.006. Epub 2018 Jan 11.

Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

Author information

1
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Breast Cancer Research Center, ACECR, Tehran, Iran. Electronic address: pshariatpanahi@ut.ac.ir.
2
School of Computer Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran. Electronic address: pooya@ipm.ir.
3
Breast Cancer Research Center, ACECR, Tehran, Iran. Electronic address: kmajidzadeh@razi.tums.ac.ir.
4
Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden; Clinical Research Center, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Moustapha.Hassan@ki.se.
5
Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Manuchehr.Abedi-Valugerdi@ki.se.

Abstract

Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs.

KEYWORDS:

5-Fluorouracil; Immunosuppression; Mathematical modeling; Myeloid-derived suppressor cell; Ordinary differential equation; l-arginine

PMID:
29337259
DOI:
10.1016/j.jtbi.2018.01.006
[Indexed for MEDLINE]

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