IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2018-07-19
Date Accepted
2018-05-29
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.
Citation
Nature, 2018, 559 (7714), pp. 363 - 369
Source Title
Publisher
NATURE PORTFOLIO
ISSN
0028-0836
eISSN
1476-4687
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics