Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Abstract

BackgroundCorticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.MethodsLymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.ResultsDexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.ConclusionsDexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0371-5) contains supplementary material, which is available to authorized users.

Differential effects of corticosteroids and anti‐TNF on tumor‐specific immune responses: implications for the management of irAEs

“…More specifically, corticosteroids are known for their capacity to directly inhibit transcription of multiple cytokine genes, including IL‐1, IL‐2, IL‐6, TNFα or IFNγ and chemokines, such as IL‐8, or to induce the expression of the anti‐inflammatory cytokine TGFβ . In addition, they have recently been shown to directly interfere with T cell activation through induction of CTLA‐4 and PD‐1 expression . In contrast, infliximab is a chimeric monoclonal antibody that only binds TNFα and thereby prevents its binding to the receptors TNF‐R1 and TNF‐R2 .…”

“…Corticosteroids can interfere with the activation, cytokine production and proliferation of T cells and induce T cell apoptosis through the glucocorticoid receptor, an intracellular receptor that upon binding translocates to the nucleus where it can induce or inhibit the transcription of target genes. 13,20 More specifically, corticosteroids are known for their capacity to directly inhibit transcription of multiple cytokine genes, including IL-1, IL-2, IL-6, TNFα or IFNγ and chemokines, such as IL-8, or to induce the expression of the antiinflammatory cytokine TGFβ. 20,21 In addition, they have recently been shown to directly interfere with T cell activation through induction of CTLA-4 and PD-1 expression.…”

“…Previous studies investigating the outcome of patients treated with steroids for the management of anti‐CTLA‐4 induced irAEs did not show a worse survival outcome for the steroid‐treated group in melanoma, however, baseline steroids diminished the survival benefits of PD‐1/PD‐L1 antibodies in lung cancer . In an ortothopic mouse model of glioma CTLA‐4 blockade was able to partially rescue T cell activity, but the timing of treatment with steroid was critical (baseline steroids had the largest impact on immunotherapy efficacy) …”

“…12 In an ortothopic mouse model of glioma CTLA-4 blockade was able to partially rescue T cell activity, but the timing of treatment with steroid was critical (baseline steroids had the largest impact on immunotherapy efficacy). 13 Thus, it remains unclear whether systemic immunosuppression may jeopardize the efficacy of the adaptive immune system in fighting cancer, or whether distinct drugs can mediate differential effects on autoimmune and anti-cancer responses. In our study, we aimed to address this issue by evaluating how clinically relevant doses of dexamethasone (a standard corticosteroid) or infliximab can modulate the activation and killing ability of tumor-infiltrating lymphocytes (TILs) in vitro.…”

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 …”