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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.

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Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK.
Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
Department of Urology, University of Padova, Padova, Italy.
Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy.
IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK.
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Università della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland.
Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne, Switzerland.
Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy.


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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