Abstract
In the advanced stages of cancers like melanoma, some of the malignant cells leave the primary tumor and infiltrate the neighboring lymph nodes (LNs). The interaction between secondary cancer and the immune response in the lymph node represents a complex process that needs to be fully understood in order to develop more effective immunotherapeutic strategies. In this process, antigen-presenting cells (APCs) approach the tumor and initiate the adaptive immune response for the corresponding antigen. They stimulate the naive CD4+ and CD8+ T lymphocytes which subsequently generate a population of helper and effector cells. On one hand, immune cells can eliminate tumor cells using cell-cell contact and by secreting apoptosis inducing cytokines. They are also able to induce their dormancy. On the other hand, the tumor cells are able to escape the immune surveillance using their immunosuppressive abilities. To study the interplay between tumor progression and the immune response, we develop two new models describing the interaction between cancer and immune cells in the lymph node. The first model consists of partial differential equations (PDEs) describing the populations of the different types of cells. The second one is a hybrid discrete-continuous model integrating the mechanical and biochemical mechanisms that define the tumor-immune interplay in the lymph node. We use the continuous model to determine the conditions of the regimes of tumor-immune interaction in the lymph node. While we use the hybrid model to elucidate the mechanisms that contribute to the development of each regime at the cellular and tissue levels. We study the dynamics of tumor growth in the absence of immune cells. Then, we consider the immune response and we quantify the effects of immunosuppression and local EGF concentration on the fate of the tumor. Numerical simulations of the two models show the existence of three possible outcomes of the tumor-immune interactions in the lymph node that coincide with the main phases of the immunoediting process: tumor elimination, equilibrium, and tumor evasion. Both models predict that the administration of EGF can promote the elimination of the secondary tumor by PD-1/PD-L1 blockade.
Highlights
Malignant cells commonly infiltrate the local, regional, and distant lymph nodes during the advanced stages of primary cancers (Dowlatshahi et al, 1997)
These experiments describe the development of primary colorectal adenocarcinoma outside of the lymph node, they are still useful for our study because mutated MC38 cells commonly migrate to neighboring lymph nodes in the advanced stages of the disease
The study shows that the immunosuppressive effect of the programmed-death 1 (PD-1)/PD-L1 pathway is sufficient to cause the evasion of the tumor
Summary
Malignant cells commonly infiltrate the local, regional, and distant lymph nodes during the advanced stages of primary cancers (Dowlatshahi et al, 1997). Among the other non-spatial models, stochastic ODEs are often used to study the effect of fluctuations and noise on the interaction between tumor and immune cells (Lefever and Horsthemke, 1979) Another class of immunecancer interaction models considers partial differential equations (PDEs) to describe the spatiotemporal aspect of this interplay. The fate decision of each cell depends on the concentrations of intracellular proteins and extracellular cytokines described, respectively, by ODEs and PDEs. We begin with the description of tumor growth dynamics in the absence of immune surveillance. We introduce the immune response and quantify the combined effect of PD-1/PD-L1 inhibition and EGF concentration on the outcome of the tumor-immune interaction in the LN Both models confirm the existence of the three regimes characterizing the immunoediting process: tumor elimination, equilibrium, and tumor evasion. They reveal that combined antiPD-1/PD-L1 therapy with growth factors can be administered in order to eradicate the tumor
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