Citation
- Authors: 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, M. B., Neeb, A., Luciano, R., Bravi, C. A., Nava-Rodrigues, D., Dolling, D., Prayer-Galetti, T., Ferreira, A., Briganti, A., Esposito, A., Barry, S., Yuan, W., Sharp, A., de Bono, J., Alimonti, A.
- Year: 2018
- Journal: Nature
- Applications: in vitro / DNA / jetPRIME
- Cell type: TRAMP-C1
Description: Mouse prostate gland carcinoma cells.
Method
For CRISPR applications.
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.