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Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.

Publication ,  Journal Article
Giles, AJ; Hutchinson, M-KND; Sonnemann, HM; Jung, J; Fecci, PE; Ratnam, NM; Zhang, W; Song, H; Bailey, R; Davis, D; Reid, CM; Park, DM; Gilbert, MR
Published in: J Immunother Cancer
June 11, 2018

BACKGROUND: Corticosteroids 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. METHODS: Lymphocyte 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. RESULTS: Dexamethasone 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. CONCLUSIONS: Dexamethasone-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.

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Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

June 11, 2018

Volume

6

Issue

1

Start / End Page

51

Location

England

Related Subject Headings

  • Mice
  • Immunotherapy
  • Immunosuppression Therapy
  • Humans
  • Female
  • Disease Models, Animal
  • Dexamethasone
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
 

Citation

APA
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MLA
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Giles, A. J., Hutchinson, M.-K., Sonnemann, H. M., Jung, J., Fecci, P. E., Ratnam, N. M., … Gilbert, M. R. (2018). Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer, 6(1), 51. https://doi.org/10.1186/s40425-018-0371-5
Giles, Amber J., Marsha-Kay N. D. Hutchinson, Heather M. Sonnemann, Jinkyu Jung, Peter E. Fecci, Nivedita M. Ratnam, Wei Zhang, et al. “Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.J Immunother Cancer 6, no. 1 (June 11, 2018): 51. https://doi.org/10.1186/s40425-018-0371-5.
Giles AJ, Hutchinson M-KND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018 Jun 11;6(1):51.
Giles, Amber J., et al. “Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.J Immunother Cancer, vol. 6, no. 1, June 2018, p. 51. Pubmed, doi:10.1186/s40425-018-0371-5.
Giles AJ, Hutchinson M-KND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, Zhang W, Song H, Bailey R, Davis D, Reid CM, Park DM, Gilbert MR. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018 Jun 11;6(1):51.
Journal cover image

Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

June 11, 2018

Volume

6

Issue

1

Start / End Page

51

Location

England

Related Subject Headings

  • Mice
  • Immunotherapy
  • Immunosuppression Therapy
  • Humans
  • Female
  • Disease Models, Animal
  • Dexamethasone
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology