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

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 and Andrea Alimonti ()
Additional contact information
Arianna Calcinotto: Oncology Institute of Southern Switzerland
Clarissa Spataro: Oncology Institute of Southern Switzerland
Elena Zagato: Oncology Institute of Southern Switzerland
Diletta Di Mitri: Oncology Institute of Southern Switzerland
Veronica Gil: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Mateus Crespo: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Gaston De Bernardis: Oncology Institute of Southern Switzerland
Marco Losa: Oncology Institute of Southern Switzerland
Michela Mirenda: Oncology Institute of Southern Switzerland
Emiliano Pasquini: Oncology Institute of Southern Switzerland
Andrea Rinaldi: Oncology Institute of Southern Switzerland
Semini Sumanasuriya: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Maryou B. Lambros: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Antje Neeb: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Roberta Lucianò: URI, IRCCS Ospedale San Raffaele
Carlo A. Bravi: URI, IRCCS Ospedale San Raffaele
Daniel Nava-Rodrigues: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
David Dolling: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Tommaso Prayer-Galetti: University of Padova
Ana Ferreira: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Alberto Briganti: URI, IRCCS Ospedale San Raffaele
Antonio Esposito: San Raffaele Scientific Institute
Simon Barry: IMED Oncology AstraZeneca, Li Ka Shing Centre
Wei Yuan: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Adam Sharp: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Johann de Bono: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Andrea Alimonti: Oncology Institute of Southern Switzerland

Nature, 2018, vol. 559, issue 7714, 363-369

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0266-0

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