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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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. © 2018 Macmillan Publishers Ltd., part of Springer Nature.
Original languageEnglish
Pages (from-to)363-369
Number of pages7
JournalNature
Volume559
Issue number7714
DOIs
Publication statusPublished - 2018

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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. https://doi.org/10.1038/s41586-018-0266-0