Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era

Abstract

Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors.

Keywords: cancer; corticosteroids; immune checkpoint inhibitors; immune-related adverse event; immunotherapy.

Figure 1

Indications for corticosteroid therapy in oncology (created with BioRender).

Figure 2

Mechanisms of glucocorticoids activity. Glucocorticoids will penetrate the plasma membrane to the cytoplasm, where they will have genomic and non-genomic effects. Following the binding of the hormone on its receptor (GR), the complex will be translocated into the nucleus and will have multiple mechanisms. (1) The binding of the complex on the response element of glucocorticoids (GRE), which will allow the expression or repression of target genes. (2) The complex binds to a transcription factor (TF) located on its response element (RE) in order to prevent or activate transcription. (3) Binding of the complex to DNA and protein substrates to prevent or activate transcription (created with BioRender).

Figure 3

Effect of glucocorticoids on the immune system. Glucocorticoids have a role on innate, adaptive, and antitumour immunity. (a) On innate immunity, during the alarm phase, they inhibit toll like receptor (TLR) signalling, which prevents the production of proinflammatory cytokines. In addition, they inhibit the release of histamine from mast cells. The mobilization phase is impacted by a decrease in leukocytes recruitment and adhesion. The resolution phase is characterized by an increased production of TGFβ (Transforming growth factor β) and interleukin 10 (IL-10). (b) On adaptive immunity, glucocorticoids play an important role because they inhibit the co-stimulation of the antigen-presenting cell (APC) to T-CD8+ or T-CD4+ lymphocytes by decreasing the expression of major histocompatibility complex (MHC) type I and II molecules and decreasing the expression of CD28 and CD80 molecules. In addition, T-cell proliferation is decreased by alteration of T-cell receptor (TCR)-initiated signalling and thus decreased IL-2 production. Glucocorticoids also have a role on the polarization and differentiation of naive CD4-T cells by inhibiting T helper 1 (Th1) and 17 (Th17) differentiation and promoting T helper 2 (Th2) and T regulator (T-reg) differentiation. (c) On anti-tumour immunity, glucocorticoids induce the expression of immune checkpoints, such as the cytotoxic T-cell associated protein 4 (CTLA4), programmed death receptor 1 (PD-1), and mucin-3 T-cell immunoglobulin (Tim-3). They also promote an exhausted and therefore dysfunctional phenotype of CD8+ lymphocytes through the co-expression of PD-1 and TIM-3 receptors (created with BioRender).

Figure 4

Challenge of glucocorticoid therapy in patients receiving immunotherapy (created with BioRender).