Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy

Abstract

BackgroundProgrammed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1.ResultsIn our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose-dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-γ, TNF-α and induction of apoptosis of T cells.ConclusionOur findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs.

Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF‐κB activation and recurrent dexamethasone administration fails to suppress it in vivo

“…Direct effect of LPS on overexpression of PD‐L1 in cancer cell lines and normal colonic mucosal cells has already been reported . Though, previous study has reported effect of DEX on PD1 expression in T cells; but to best of our knowledge, our data for the first time shows that DEX alone can upregulate pdl‐1 expression in MAT‐LyLu tumour in vivo. The effect of DEX in upregulating pdl‐1 in MAT‐LyLu cancer cells and/or in stromal cells (mostly in APCs) might be due to the direct and/or indirect effect of DEX on these cells, which needs further investigation.…”

PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction

“…Conversely, we now demonstrate that interactions between CD11 + antigen presenting cells and CD8 + T cells are significantly prolonged when CD8 + T cells are deficient in PD-1, which results in their differentiation towards an effector memory phenotype and an inability to induce tolerance. Previous kinetic studies have shown a dynamic course of PD-1 expression on T cells with the highest expression levels and a higher proportion of T cells expressing PD-1 early after activation followed by a subsequent decline (30). Two previous studies have examined how PD-1 regulates T cell motility and the formation of immune synapses.…”

“…Previous kinetic studies have shown a dynamic course of PD-1 expression on T cells with the highest expression levels and a higher proportion of T cells expressing PD-1 early after activation followed by a subsequent decline. 30 Two previous studies have examined how PD-1 regulates T cell motility and the formation of immune synapses. Similar to our findings, Fife observed in a model of autoimmunity that PD-L1 blockade was associated with prolonged interactions between CD4 + T lymphocytes and dendritic cells in antigen-bearing lymph nodes, resulting in the activation of T cells and their production of proinflammatory cytokines.…”

Modulation of macrophage phenotype via phagocytosis of drug‐loaded microparticles

“…However, systemic Dex administration has failed in a number of clinical trials and cannot be tolerated by patients over long treatment regimens because of adverse side effects . This is most likely because systemically administered Dex affects a broad population of cells and results in non‐specific immunosuppression, especially of the adaptive immune system …”

“…[22][23][24][25][26] This is most likely because systemically administered Dex affects a broad population of cells and results in non-specific immunosuppression, especially of the adaptive immune system. 27,28 Clearly, there is a need to develop a strategy to selectively modulate macrophage behavior toward an anti-inflammatory, pro-regeneration phenotype without the detrimental effects of systemic corticosteroid administration. To address these challenges, we postulate that selective delivery of Dex to macrophages may allow control over macrophage behavior without inducing systemic side effects.…”