Journal
NATURE
Volume 559, Issue 7714, Pages 363-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-018-0266-0
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Funding
- ERC consolidator [683136]
- Swiss Cancer League [KFS4267-08-2017]
- Dr. Josef Steiner Foundation
- Swiss Card-Onco-Grant of Alfred and Annemarie von Sick grant
- Helmut Horten Foundation
- SNSF [310030_176045]
- PCUK [RIA15-ST2-018]
- IBSA Foundation
- Movember Foundation
- Prostate Cancer UK
- US Department of Defense
- Prostate Cancer Foundation
- Stand Up To Cancer
- Cancer Research UK
- UK Department of Health through an Experimental Cancer Medicine Centre grant
- Medical Research Council
- Academy of Medical Sciences
- Swiss National Science Foundation (SNF) [310030_176045] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MR/M018318/1] Funding Source: UKRI
- European Research Council (ERC) [683136] Funding Source: European Research Council (ERC)
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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.
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