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

A Calcinotto, C Spataro, E Zagato, D Di Mitri, V Gil, M Crespo, G De Bernardis, M Losa, M Mirenda, E Pasquini, A Rinaldi, S Sumanasuriya, MB Lambros, A Neeb, R Lucianò, CA Bravi, D Nava-Rodrigues, D Dolling, T Prayer-Galetti, A FerreiraA Briganti, A Esposito, S Barry, W Yuan, A Sharp, J De Bono, A Alimonti

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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. © 2018 Macmillan Publishers Ltd., part of Springer Nature.
Original languageEnglish
Pages (from-to)363-369
Number of pages7
Issue number7714
Publication statusPublished - 2018


Cite this

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., ... Alimonti, A. (2018). IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature, 559(7714), 363-369.