Mathematical Modeling of Interleukin-27 Induction of Anti-Tumor T Cells Response

Abstract

Interleukin-12 is a pro-inflammatory cytokine which promotes Th1 and cytotoxic T lymphocyte activities, such as Interferon- secretion. For this reason Interleukin-12 could be a powerful therapeutic agent for cancer treatment. However, Interleukin-12 is also excessively toxic. Interleukin-27 is an immunoregulatory cytokine from the Interleukin-12 family, but it is not as toxic as Interleukin-12. In recent years, Interleukin-27 has been considered as a potential anti-tumor agent. Recent experiments in vitro and in vivo have shown that cancer cells transfected with IL-27 activate CD8+ T cells to promote the secretion of anti-tumor cytokines Interleukin-10, although, at the same time, IL-27 inhibits the secretion of Interferon- by CD8+ T cells. In the present paper we develop a mathematical model based on these experimental results. The model involves a dynamic network which includes tumor cells, CD8+ T cells and cytokines Interleukin-27, Interleukin-10 and Interferon-. Simulations of the model show how Interleukin-27 promotes CD8+ T cells to secrete Interleukin-10 to inhibit tumor growth. On the other hand Interleukin-27 inhibits the secretion of Interferon- by CD8+ T cells which somewhat diminishes the inhibition of tumor growth. Our numerical results are in qualitative agreement with experimental data. We use the model to design protocols of IL-27 injections for the treatment of cancer and find that, for some special types of cancer, with a fixed total amount of drug, within a certain range, continuous injection has better efficacy than intermittent injections in reducing the tumor load while the treatment is ongoing, although the decrease in tumor load is only temporary.

Genetic association between IL-27 rs153109 polymorphism and cancer risk in Chinese population: a meta-analysis

“…Recently, a mathematic model was published to calculate the amount of IL-27 that needs to be injected in mice to reject the tumor (27). One may deliver IL-27 or IL-10 to colon cancer via yeast that is programmed to express IL-27 or IL-10, or infect tumor cells with virus that are designed to produce IL-27 and thus generate tumor rejection (27). Other therapies may involve modification of IL-27 receptor or JAK/STAT1 pathway.…”

Exosomal miRs in Lung Cancer: A Mathematical Model

“…We accordingly assume that the proliferation rate of cancer cells through the MAPK pathway is higher than the proliferation rate through the AKT pathway, and take λ C 1 = 2 λ C 2 . We also assume that in steady state and take λ C = 0.46 day −1 [77]. Hence λ C 1 = (4/3) λ C = 0.6133 day −1 and λ C 2 = (2/3) λ C = 0.3067 day −1 .…”

“…Diffusion coefficients : We take D C = 8.64 × 10 −7 cm 2 day −1 [77]. Diffusion of a sphere is inversely proportional to its diameter.…”

“…Then we get . By [79], we have the relation , where D V and M V are the diffusion coefficient and molecular weight of vascular endothelial growth factor (VEGF), respectively, and D V = 8.64 × 10 −2 [77], and M V = 24 kDa [80]. The molecular weight of miR-21 is M m 1 = 7 kDa, hence D m 1 = 0.13028 cm 2 day −1 , and similarly D m 2 = 0.13028 cm 2 day −1 .…”

Skeletal muscle signal peptide optimization for enhancing propeptide or cytokine secretion

“…Therefore, we anticipate that certain tumors or diseases may necessitate a higher-level of cytokine expression and/or secretion into serum for reaching full therapeutic efficacy. Using mathematical models [4], the serum levels needed for IL-27 efficacy could be significantly higher for more aggressive tumors, such as >1300 pg/ml. Therefore, it is critical to develop strategies to enhance secretion of cytokines from muscle so therapeutic levels can be achieved in serum for eliminating aggressive or difficult to treat tumors.…”