The glucocorticoid receptor modulator relacorilant reverses the immunosuppressive effects of cortisol.

Autor: Greenstein AE; Corcept Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USA. Electronic address: agreenstein@corcept.com., Hunt HJ; Corcept Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USA. Electronic address: hhunt@corcept.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2023 Jul; Vol. 120, pp. 110312. Date of Electronic Publication: 2023 May 23.
DOI: 10.1016/j.intimp.2023.110312
Abstrakt: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, apoptosis, and immune-cell trafficking. The degree to which endogenous cortisol blunts the anti-tumor immune response checkpoint inhibitors stimulate had not been assessed. We addressed this question using relacorilant, a selective GR modulator (SGRM) that competitively antagonizes the effects of cortisol activity. GR expression in human tumor and immune cells positively correlated with PD-L1 expression and tumor infiltration of Th2 and T reg cells, and negatively correlated with Th1-cell infiltration. In vitro, cortisol inhibited, and relacorilant restored, T-cell activation and pro-inflammatory cytokine secretion in human peripheral blood mononuclear cells. In the ovalbumin-expressing EG7 and MC38 immune-competent tumor models, relacorilant significantly improved anti-PD-1 antibody efficacy and showed favorable effects on antigen-specific T-cells and systemic TNFα and IL-10. These data characterize the broad immunosuppressive effects of endogenous cortisol and highlight the potential of combining an SGRM with an immune checkpoint inhibitor.
Competing Interests: Declaration of Competing Interest AEG and HJH are employees and stockholders of Corcept Therapeutics, the company developing relacorilant. The authors have no additional relevant financial interests.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
Externí odkaz: