IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.
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Date
2018-07-19Author
Calcinotto, A
Spataro, C
Zagato, E
Di Mitri, D
Gil, V
Crespo, M
De Bernardis, G
Losa, M
Mirenda, M
Pasquini, E
Rinaldi, A
Sumanasuriya, S
Lambros, MB
Neeb, A
Lucianò, R
Bravi, CA
Nava-Rodrigues, D
Dolling, D
Prayer-Galetti, T
Ferreira, A
Briganti, A
Esposito, A
Barry, S
Yuan, W
Sharp, A
de Bono, J
Alimonti, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Animals
Humans
Mice
Phenylthiohydantoin
Receptors, Interleukin
Receptors, Androgen
Androgens
Signal Transduction
Cell Proliferation
Cell Survival
Male
Interleukin-23
Nuclear Receptor Subfamily 1, Group F, Member 3
Androgen Receptor Antagonists
Prostatic Neoplasms, Castration-Resistant
Myeloid-Derived Suppressor Cells
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2018-05-29
License start date
2018-07
Citation
Nature, 2018, 559 (7714), pp. 363 - 369
Publisher
NATURE PORTFOLIO