Mathematical Modeling of Interleukin-35 Promoting Tumor Growth and Angiogenesis

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 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.

Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

“…showed that overexpression of IL-35 inhibited cell growth and increased apoptosis sensitivity of different human cancer cell lines. In contrast, most studies have demonstrated that IL-35 is an autocrine growth factor [13], which promotes tumor growth through different mechanisms, including enhancement of proliferation and loss of control of tumor cell growth, inhibition of apoptosis, and promotion of angiogenesis, extravasation, and metastasis [13,15,35,36]. To the best of our knowledge, the current in vitro results provided the first data about on the influence of IL-35 to bioactivity of NSCLC cell lines.…”

“…IL-35 has anti-inflammatory and immunoregulatory properties [9,11], and inhibits angiogenesis through different signaling pathways [12]. It also plays pivotal roles in the pathogenesis of cancers, as it promotes the growth of cancer cells through the enhancement of proliferation and angiogenesis, inhibition of apoptosis [13][14][15], and limitation of anti-tumor T cells immunity [16]. In addition, elevated IL-35 levels are also associated with cancer progression, aggressiveness, and recurrence [17][18][19][20].…”

Qualitative analysis of kinetic-based models for tumor-immune system interaction

“…They could be included at the price of additional technical, but not essential, difficulties. Analogously, it is well known that there exists a great variety of interleukins, of different origin and with quite different behaviour and pecularities (see for instance the seminal paper [22] and the recent work [26]), but in our mathematical model we are mainly interested in capturing their overall effect as immune system supporters, which will be described in a statistical average manner by single interaction rates. For a numerical solution of the resulting integro-differential system with quadratic nonlinearities, a suitable discretization technique is needed anyhow.…”

Demystifying the cytokine network: Mathematical models point the way

“…In one study an ODE model was used to optimize the treatment protocol of IL-21 given as an anti-tumor therapeutic [98], demonstrating that lower doses given twice a day just as effective and less toxic than higher doses given once a day [98]. Another model examined the tumor-promoting effects of IL-35 [107] and also studied the effects of administering an anti-IL-35 reagent as a therapeutic. This study suggested that continuous administration of the anti-IL-35 would be most efficacious in reducing the tumor load [107].…”

“…Another model examined the tumor-promoting effects of IL-35 [107] and also studied the effects of administering an anti-IL-35 reagent as a therapeutic. This study suggested that continuous administration of the anti-IL-35 would be most efficacious in reducing the tumor load [107]. Another therapeutic approach in cancer has been the coupling of inflammatory cytokines, such as IL-2, to antibodies specific for tumor-associated antigens; so called immunocytokines [108].…”