IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.
Details
Serval ID
serval:BIB_33B2C3A79F30
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.
Journal
Nature
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
07/2018
Peer-reviewed
Oui
Volume
559
Number
7714
Pages
363-369
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Publication Status: ppublish
Abstract
Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.
Keywords
Androgen Receptor Antagonists/pharmacology, Androgen Receptor Antagonists/therapeutic use, Androgens/deficiency, Animals, Cell Proliferation, Cell Survival, Humans, Interleukin-23/antagonists & inhibitors, Interleukin-23/blood, Interleukin-23/immunology, Interleukin-23/metabolism, Male, Mice, Myeloid-Derived Suppressor Cells/cytology, Myeloid-Derived Suppressor Cells/immunology, Myeloid-Derived Suppressor Cells/metabolism, Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism, Phenylthiohydantoin/analogs & derivatives, Phenylthiohydantoin/pharmacology, Phenylthiohydantoin/therapeutic use, Prostatic Neoplasms, Castration-Resistant/blood, Prostatic Neoplasms, Castration-Resistant/metabolism, Prostatic Neoplasms, Castration-Resistant/pathology, Prostatic Neoplasms, Castration-Resistant/therapy, Receptors, Androgen/metabolism, Receptors, Interleukin/metabolism, Signal Transduction
Pubmed
Web of science
Create date
29/06/2018 16:49
Last modification date
20/08/2019 14:19