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Nature. 2018 Jul;559(7714):363-369. doi: 10.1038/s41586-018-0266-0. Epub 2018 Jun 27.

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.

Author information

1
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
2
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK.
3
Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
4
Department of Urology, University of Padova, Padova, Italy.
5
Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy.
6
IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK.
7
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. andrea.alimonti@ior.iosi.ch.
8
Università della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland. andrea.alimonti@ior.iosi.ch.
9
Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne, Switzerland. andrea.alimonti@ior.iosi.ch.
10
Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy. andrea.alimonti@ior.iosi.ch.

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.

PMID:
29950727
DOI:
10.1038/s41586-018-0266-0

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