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.
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, M.B. Lambros, A. Neeb, R. Luciano, C.A. Bravi, D. Nava-Rodrigues, D. Dolling, T. Prayer-Galetti, A. Ferreira, A. Briganti, A. Esposito, S. Barry, W. Yuan, A. Sharp, J. De Bono, A. Alimonti. - In: NATURE. - ISSN 0028-0836. - 559:7714(2018 Jun), pp. 363-369. [10.1038/s41586-018-0266-0]
IL-23 secreted by myeloid cells drives castration-resistant prostate cancer
E. Zagato;M. Mirenda;W. Yuan;
2018
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.File | Dimensione | Formato | |
---|---|---|---|
s41586-018-0266-0_compressed.pdf
accesso riservato
Descrizione: Article
Tipologia:
Publisher's version/PDF
Dimensione
1.79 MB
Formato
Adobe PDF
|
1.79 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.