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 Andrea Bravi,Daniel Nava-Rodrigues,David Dolling,Tommaso Prayer-Galetti,Ana Ferreira,Alberto Briganti,Antonio Esposito,Simon T. Barry,Wei Yuan,Adam Sharp,Johann S. de Bono,Andrea Alimonti +26 more
TLDR
Results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner and Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.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.read more
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