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Mathematical modeling of Interleukin-35 promoting tumor growth and angiogenesis.

Liao KL, Bai XF, Friedman A - PLoS ONE (2014)

Bottom Line: In the present paper we develop a mathematical model based on these experimental results.We include in the model an anti-IL-35 drug as treatment.We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8[Formula: see text] T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased.

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Evolution of cells and cytokines for J558-IL-35 and J558-Ctrl mice models.Panels (A) to (J) show the profiles of the total numbers of tumor cells, M-CSF, MDSCs, , Tregs, TGF-, CD8 T cells, VEGF, endothelial cells, and oxygen, for cases (i) and (ii). The solid curve is for J558-IL-35 tumor cells with large  production (case (ii)) and the dashed curve is for J558-Ctrl tumor cells (case (i)).
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pone-0110126-g003: Evolution of cells and cytokines for J558-IL-35 and J558-Ctrl mice models.Panels (A) to (J) show the profiles of the total numbers of tumor cells, M-CSF, MDSCs, , Tregs, TGF-, CD8 T cells, VEGF, endothelial cells, and oxygen, for cases (i) and (ii). The solid curve is for J558-IL-35 tumor cells with large production (case (ii)) and the dashed curve is for J558-Ctrl tumor cells (case (i)).

Mentions: The results of Wang et al. [1] were reported weeks after injection of tumor cells into mice. Hence, we compare our simulations at the end of the second week with the results in [1]. In Figure 3(C), the ratio for MDSC of J558-IL-35 to J558-Ctrl is , which is the same as Figure five A in [1]. In Figure 3(H), the ratio for VEGF of J558-IL-35 to J558-Ctrl is , which is the approximately same as Figure four D in [1]. Next, we compare the ratio for Treg/CD8 T cells of J558-IL-35 to J558-Ctrl with the result in [1]. But, in [1], they only showed the percentages of CD8/CD45, of CD4/CD45, and of Foxp3/CD4. By combining these results (Figures seven B, seven D, and seven E in [1]), we find that this ratio (for Treg/CD8 T cells) is . From our Figures 3(E) and 3(H), we compute the ratio of J558-IL-35 to J558-Ctrl to be . Thus in all the above three cases we get a very good quantitative fit with the experimental results of Wang et al. [1]. Finally, from Figure 3(A), we see that for tumor cells the ratio of J558-IL-35 to J558-Ctrl is , which is somewhat less than the ratio for the tumor volume of B16-IL-35 mice to B16-Ctrl mice in Figure three F in [1], and significantly less for J558-IL-35 mice. This discrepancy may be explained by the fact that in vivo the arrival of MDSCs to the tumor microenvironment is somewhat delayed and therefore the number of CD8 T cells in the control case is significantly less than in the J558-IL-35 case, while (for simplicity) our model does not include such a time delay.


Mathematical modeling of Interleukin-35 promoting tumor growth and angiogenesis.

Liao KL, Bai XF, Friedman A - PLoS ONE (2014)

Evolution of cells and cytokines for J558-IL-35 and J558-Ctrl mice models.Panels (A) to (J) show the profiles of the total numbers of tumor cells, M-CSF, MDSCs, , Tregs, TGF-, CD8 T cells, VEGF, endothelial cells, and oxygen, for cases (i) and (ii). The solid curve is for J558-IL-35 tumor cells with large  production (case (ii)) and the dashed curve is for J558-Ctrl tumor cells (case (i)).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4214702&req=5

pone-0110126-g003: Evolution of cells and cytokines for J558-IL-35 and J558-Ctrl mice models.Panels (A) to (J) show the profiles of the total numbers of tumor cells, M-CSF, MDSCs, , Tregs, TGF-, CD8 T cells, VEGF, endothelial cells, and oxygen, for cases (i) and (ii). The solid curve is for J558-IL-35 tumor cells with large production (case (ii)) and the dashed curve is for J558-Ctrl tumor cells (case (i)).
Mentions: The results of Wang et al. [1] were reported weeks after injection of tumor cells into mice. Hence, we compare our simulations at the end of the second week with the results in [1]. In Figure 3(C), the ratio for MDSC of J558-IL-35 to J558-Ctrl is , which is the same as Figure five A in [1]. In Figure 3(H), the ratio for VEGF of J558-IL-35 to J558-Ctrl is , which is the approximately same as Figure four D in [1]. Next, we compare the ratio for Treg/CD8 T cells of J558-IL-35 to J558-Ctrl with the result in [1]. But, in [1], they only showed the percentages of CD8/CD45, of CD4/CD45, and of Foxp3/CD4. By combining these results (Figures seven B, seven D, and seven E in [1]), we find that this ratio (for Treg/CD8 T cells) is . From our Figures 3(E) and 3(H), we compute the ratio of J558-IL-35 to J558-Ctrl to be . Thus in all the above three cases we get a very good quantitative fit with the experimental results of Wang et al. [1]. Finally, from Figure 3(A), we see that for tumor cells the ratio of J558-IL-35 to J558-Ctrl is , which is somewhat less than the ratio for the tumor volume of B16-IL-35 mice to B16-Ctrl mice in Figure three F in [1], and significantly less for J558-IL-35 mice. This discrepancy may be explained by the fact that in vivo the arrival of MDSCs to the tumor microenvironment is somewhat delayed and therefore the number of CD8 T cells in the control case is significantly less than in the J558-IL-35 case, while (for simplicity) our model does not include such a time delay.

Bottom Line: In the present paper we develop a mathematical model based on these experimental results.We include in the model an anti-IL-35 drug as treatment.We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Mathematical Biosciences Institute, The Ohio State University, Columbus, Ohio, United States of America.

ABSTRACT
Interleukin-35 (IL-35), a cytokine from the Interleukin-12 cytokine family, has been considered as an anti-inflammatory cytokine which promotes tumor progression and tumor immune evasion. It has also been demonstrated that IL-35 is secreted by regulatory T cells. Recent mouse experiments have shown that IL-35 produced by cancer cells promotes tumor growth via enhancing myeloid cell accumulation and angiogenesis, and reducing the infiltration of activated CD8[Formula: see text] T cells into tumor microenvironment. In the present paper we develop a mathematical model based on these experimental results. We include in the model an anti-IL-35 drug as treatment. The extended model (with drug) is used to design protocols of anti-IL-35 injections for treatment of cancer. We find that with a fixed total amount of drug, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing. We also find that the percentage of tumor reduction under anti-IL-35 treatment improves when the production of IL-35 by cancer is increased.

Show MeSH
Related in: MedlinePlus