Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Abstract

Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to "confuse" the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

Keywords: PD-1/PD-L1; cancer; glucocorticoids; immune response.

Figure 1

Regulation of PD-1/PD-L1 expression. (A) Upstream signaling pathways leading to PD-1 transcription; (B) signaling pathways involved in PD-L1 transcription. Multiple pathways promote PD-L1 expression. Red = inhibitory signaling; black = activating signaling.

Figure 2

PD-1/PD-L1 inhibitory pathway. APCs present antigens released from tumor cells to T cells, leading to T cell activation and PD-1 expression. PD-1 binds PD1-L1/2 expressed on the surface of both APCs and tumor cells, leading to inhibition of TCR and CD28 signaling. This results in an inhibition of cell proliferation, activation, and differentiation. Th-1 and Th-17 differentiation is inhibited, while Tregs are increased. The upregulation of PTEN participates in the latter.

Figure 3

Effects of glucocorticoids on innate and adaptive immunity. Cells involved in GC-mediated immunosuppression. Red = inhibitory signaling; black = activating signaling.

Figure 4

The effects of glucocorticoids on tumor cells.

Figure 5

Interaction between glucocorticoid and PD-1/PDL-1 signals. Blocking antibodies (anti-PD-1/PD-L1) induce T cell reactivation by restoring T cell proliferation and cytokine production. GCs counteract this effect by inhibiting T cell activation through several mechanisms. GC binding to the GR induces PD-1 transcription in T cells and NK cells, hindering the efficacy of blocking therapy. GCs also upregulate PD1-L in DC cells, through GILZ expression, decreasing the efficacy of immunotherapy. In contrast, GCs inhibit PD-L1 on tumor cells, thus exerting anti-tumor activity GC and anti-PD-1/PDL-1 immunotherapy have different effects on Tregs. In some cases, they both increase Tregs; in other cases, GCs increase Tregs while immunotherapy decreases them.