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.
Nature. 2018 Jun 27 [Epub]
Arianna Calcinotto, Clarissa Spataro, Elena Zagato, Diletta Di Mitri, Veronica Gil, Mateus Crespo, Gaston De Bernardis, Marco Losa, Michela Mirenda, Emiliano Pasquini, Andrea Rinaldi, Semini Sumanasuriya, Maryou B Lambros, Antje Neeb, Roberta Lucianò, Carlo A Bravi, Daniel Nava-Rodrigues, David Dolling, Tommaso Prayer-Galetti, Ana Ferreira, Alberto Briganti, Antonio Esposito, Simon Barry, Wei Yuan, Adam Sharp, Johann de Bono, Andrea Alimonti
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. .