Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy
Amber J Giles1, Marsha-Kay N D Hutchinson2, Heather M Sonnemann2
1Neuro-Oncology Branch, CCR, NCI, National Institutes of Health, 37 Convent Dr. Bldg. 37, Rm. 1142B, Bethesda, MD, 20892, USA. amber.giles@nih.gov.
Journal for Immunotherapy of Cancer
|June 13, 2018
Summary
Dexamethasone suppresses T cells by hindering the CD28 pathway, but CTLA-4 blockade can partially overcome these effects during cancer immunotherapy. This research offers guidance on using corticosteroids with immune checkpoint inhibitors.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Corticosteroids manage edema and immune-related adverse events (irAEs) in cancer patients.
- The impact of corticosteroids on immunotherapy efficacy remains unclear.
- Understanding this interaction is crucial for optimizing cancer treatment.
Purpose of the Study:
- To investigate dexamethasone's effects on T cell activation and proliferation during immune checkpoint blockade.
- To provide evidence-based guidance for concurrent corticosteroid and immunotherapy use.
- To inform clinical decisions regarding cancer treatment strategies.
Main Methods:
- Assessed T cell proliferation, differentiation, and cytokine production under dexamethasone exposure.
- Utilized CD3/CD28 stimulation and CTLA-4 blockade (ipilimumab) in human T cells.
- Evaluated in vivo effects in a mouse glioma model, analyzing immune populations via flow cytometry.
Main Results:
- Dexamethasone upregulated CTLA-4 and inhibited CD28-mediated T cell activation and differentiation, particularly in naïve T cells.
- CTLA-4 blockade, but not PD-1 blockade, partially reversed dexamethasone's inhibitory effects.
- In mice, CTLA-4 blockade increased IFNγ-producing T cells and improved survival during combined treatment.
Conclusions:
- Dexamethasone suppresses T cells by attenuating the CD28 pathway.
- CTLA-4 blockade offers a potential strategy to mitigate dexamethasone's immunosuppressive effects during immunotherapy.
- This finding supports careful consideration of corticosteroid use alongside immune checkpoint inhibitors in cancer therapy.
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