New research shows that myeloid-derived suppressor cells (MDSCs) drive progression to castration-resistant prostate cancer (CRPC) by secreting interleukin 23 (IL-23).
MDSCs were enriched in CRPC biopsy specimens compared with castration-sensitive prostate cancer (CSPC) specimens, and surgical castration increased tumour-infiltrating MDSC numbers in mouse models that develop CRPC upon androgen withdrawal. In vitro, MDSC-derived conditioned medium increased proliferation, survival, and androgen receptor (AR) target gene transcription under androgen-deprived conditions, suggesting that paracrine factors regulate CRPC emergence. Indeed, pharmacological depletion of tumour-infiltrating MDSCs delayed CRPC progression in castrated mice.
IL-23 was identified as the major MDSC-derived factor driving CRPC. Notably, MDSC-secreted IL-23 levels were markedly higher in mouse and human CRPC tumours than CSPCs. Plasma IL-23 levels were also increased in patients with CRPC and correlated with MDSC infiltration. In a functional validation, conditioned medium from MDSCs derived from Il23+/+ mice, but not Il23−/− mice, induced proliferation, survival, and AR activity in androgen-dependent prostate cancer cells and organoids; similar findings were reported in vivo. Subsequent mechanistic experiments identified IL-23R–STAT3–RORγ signalling as the major pathway downstream of IL-23.
Notably, although treatment with AR antagonist enzalutamide alone was ineffective, the addition of an anti-IL-23 antibody reduced tumour volume, proliferation, and AR activity, and induced apoptosis, in mouse tumours, illustrating the therapeutic relevance.
These findings reveal a novel mechanism of immune-mediated resistance to androgen deprivation therapy (ADT) that could be exploited therapeutically. “Together with J. De Bono at ICR, we aim to run a clinical trial to assess if anti-IL-23 antibodies can improve ADT efficacy and revert ADT resistance in metastatic CRPC,” concludes author Andrea Alimonti.
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Original article
Calcinotto, A. et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature https://doi.org/10.1038/s41586-018-0266-0 (2018)
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Bradley, C.A. Myeloid-derived IL-23 drives CRPC. Nat Rev Urol 15, 528 (2018). https://doi.org/10.1038/s41585-018-0059-0
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DOI: https://doi.org/10.1038/s41585-018-0059-0