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The Prostacyclin Receptor is a Nrf2-regulated Immune Checkpoint in CD8+ T cells

ABSTRACT: Understanding how circulating metabolites enforce pathways in dysfunctional immune cells may illuminate modes of intervention directed at reviving immune function. The NRF2 pathway is the most widely documented cytoprotective axis in land-dwelling eukaryotes. However, the role of this pathway in CD8+ T cells—which seek and destroy tumors and pathogen infected cells—has yet to be elucidated. Our lab has conducted a RNAseq meta-analysis of CD8+ T cells upon tumor, viral and bacterial inoculation. Curiously, the NRF2 pathway was robustly upregulated in dysfunctional CD8+T cells. To further investigate the role of NRF2 in these contexts we developed a mouse model whereby the NRF2 axis is permanently hyperactivated in CD8+ T cells, hereafter referred to as NRF2Hi. Our in vivo data demonstrate that NRF2Hi CD8+ T cells offer little overall cytoprotection and poorly control tumors and pathogens versus wildtype (WT) control CD8+ T cells. To understand why upregulation of the NRF2 axis could be unfavorable to CD8+ T cell function we conducted RNAseq on NRF2Hi versus WT cells upon viral infection of mice. We found that NRF2Hi cells massively upregulate the prostacyclin receptor (PTGIR), which binds to prostacyclin—a circulating metabolite of arachidonic acid that has only been investigated in vasodilation and is seemingly benign to CD8+ T cells. To decipher the role of PTGIR in CD8+ T cells, we silenced its expression and observed a revival of CD8+ T cell function, significantly reducing tumor and pathogen burden. Collectively, our data illuminate a NRF2-regulated immune checkpoint, PTGIR. Interventions that suppress the interaction between PTGIR and prostacyclin may serve therapeutic benefit in clinical contexts such as cancer and chronic pathogen infections.

ORGANISM(S): Mus musculus

PROVIDER: GSE244465 | GEO | 2024/07/17

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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The Prostacyclin Receptor is a Nrf2-regulated Immune Checkpoint in CD8+ T cells

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