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Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3

ABSTRACT: Approximately 30% of breast cancer survivors deemed ‘free of disease’ will experience locoregional or metastatic recurrence even up to 30 years post initial diagnosis, yet how residual/dormant tumor cells escape immunity elicited by the primary tumor remains unclear. We demonstrate that intrinsically dormant tumor cells are indeed recognized and lysed by antigen-specific T cells in vitro and elicit robust immune responses in vivo. However, despite close proximity to CD8+ killer T cells, dormant tumor cells themselves support early accumulation of protective FoxP3+ T regulatory cells (Tregs), which can be targeted to reduce tumor burden. These intrinsically dormant tumor cells maintain a hybrid epithelial/mesenchymal or stem-like state, which is associated with immune dysfunction, and we find the tumor-derived stem/basal gene Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) is critical for Treg inhibition of CD8+ T cells. We also demonstrate that DKK3 promotes immune-mediated progression of proliferative tumors and is significantly associated with poor survival and immune suppression in human breast cancers. Together, these findings reveal that latent tumors can use fundamental mechanisms of tolerance to alter the T cell microenvironment and subvert immune detection. Thus, targeting these pathways, such as DKK3, may help render dormant tumors susceptible to immunotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE240021 | GEO | 2023/11/06

REPOSITORIES: GEO

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Project description:This ordinary differential equation model simulating the interactions between tumor and immune cells is detailed in the publication: Ahmed M. Makhlouf, Lamiaa El-Shennawy, Hesham A. Elkaranshawy, "Mathematical Modelling for the Role of CD4+T Cells in Tumor-Immune Interactions", Comput Math Methods Med. 2020 Feb 19;2020:7187602. doi: 10.1155/2020/7187602 Comment: This no treatment model is described by equations 1-7 of the publication manuscript. Abstract: Mathematical modelling has been used to study tumor-immune cell interaction. Some models were proposed to examine the effect of circulating lymphocytes, natural killer cells, and CD8+T cells, but they neglected the role of CD4+T cells. Other models were constructed to study the role of CD4+T cells but did not consider the role of other immune cells. In this study, we propose a mathematical model, in the form of a system of nonlinear ordinary differential equations, that predicts the interaction between tumor cells and natural killer cells, CD4+T cells, CD8+T cells, and circulating lymphocytes with or without immunotherapy and/or chemotherapy. This system is stiff, and the Runge–Kutta method failed to solve it. Consequently, the “Adams predictor-corrector” method is used. The results reveal that the patient’s immune system can overcome small tumors; however, if the tumor is large, adoptive therapy with CD4+T cells can be an alternative to both CD8+T cell therapy and cytokines in some cases. Moreover, CD4+T cell therapy could replace chemotherapy depending upon tumor size. Even if a combination of chemotherapy and immunotherapy is necessary, using CD4+T cell therapy can better reduce the dose of the associated chemotherapy compared to using combined CD8+T cells and cytokine therapy. Stability analysis is performed for the studied patients. It has been found that all equilibrium points are unstable, and a condition for preventing tumor recurrence after treatment has been deduced. Finally, a bifurcation analysis is performed to study the effect of varying system parameters on the stability, and bifurcation points are specified. New equilibrium points are created or demolished at some bifurcation points, and stability is changed at some others. Hence, for systems turning to be stable, tumors can be eradicated without the possibility of recurrence. The proposed mathematical model provides a valuable tool for designing patients’ treatment intervention strategies.

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Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3

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