Abstract
Positive feedback loops drive immune cell polarization toward a pro-tumor phenotype that accentuates immunosuppression and tumor angiogenesis. This phenotypic switch leads to the escape of cancer cells from immune destruction. These positive feedback loops are generated by cytokines such as TGF-β, Interleukin-10 and Interleukin-4, which are responsible for the polarization of monocytes and M1 macrophages into pro-tumor M2 macrophages, and the polarization of naive helper T cells intopro-tumor Th2 cells. In this article, we present a deterministic ordinary differential equation (ODE) model that includes key cellular interactions and cytokine signaling pathways that lead to immune cell polarization in the tumor microenvironment. The model was used to simulate various cancer treatments in silico. We identified combination therapies that consist of M1 macrophages or Th1 helper cells, coupled with an anti-angiogenic treatment, that are robust with respect to immune response strength, initial tumor size and treatment resistance. We also identified IL-4 and IL-10 as the targets that should be neutralized in order to make these combination treatments robust with respect to immune cell polarization. The model simulations confirmed a hypothesis based on published experimental evidence that a polarization into the M1 and Th1 phenotypes to increase the M1-to-M2 and Th1-to-Th2 ratios plays a significant role in treatment success. Our results highlight the importance of immune cell reprogramming as a viable strategy to eradicate a highly vascularized tumor when the strength of the immune response is characteristically weak and cell polarization to the pro-tumor phenotype has occurred.
Highlights
IntroductionThe differentiation and polarization of certain immune cells into pro-inflammatory and anti-inflammatory cells confer the immune system with versatility to exhibit a strong, but controlled, response against invading pathogens and foreign antigens
We identified combination therapies that consist of M1 macrophages or Th1 helper cells, coupled with an anti-angiogenic treatment, that are robust with respect to immune response strength, initial tumor size and treatment resistance
We focused on increasing the M1-to-M2 macrophage and the Th1-to-Th2 helper cell ratios by injecting anti-tumor polarized cells (M1 macrophages and Th1 helper cells) and by disrupting pro-tumor positive feedback loops driven by TGF-β, IL-4 and IL-10
Summary
The differentiation and polarization of certain immune cells into pro-inflammatory and anti-inflammatory cells confer the immune system with versatility to exhibit a strong, but controlled, response against invading pathogens and foreign antigens This is made possible by the initial generation of a strong inflammatory response that is subsequently regulated and attenuated by an anti-inflammatory response once the invading agents have been destroyed. When healthy cells mutate and become cancerous, immune cells such as natural killer cells and cytotoxic T lymphocytes (CTL) try to eliminate these anomalous cells They do so by infiltrating the tumor site and releasing proteins that destroy the cancer cell membrane (Perforin), and release enzymes that lead to cancer cell apoptosis (Granzyme B) [2]. A high Th1-to-Th2 ratio increases the likelihood of tumor destruction, whereas a ratio close to zero increases the likelihood of tumor survival [7]
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