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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Androgen Receptor Antagonists / pharmacology
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Androgen Receptor Antagonists / therapeutic use
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Androgens / deficiency
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Animals
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Benzamides
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Cell Proliferation
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Cell Survival
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Humans
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Interleukin-23 / antagonists & inhibitors*
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Interleukin-23 / blood
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Interleukin-23 / immunology
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Interleukin-23 / metabolism*
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Male
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Mice
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Myeloid-Derived Suppressor Cells / cytology
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Myeloid-Derived Suppressor Cells / immunology
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Myeloid-Derived Suppressor Cells / metabolism*
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Nitriles
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Phenylthiohydantoin / analogs & derivatives
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Phenylthiohydantoin / pharmacology
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Phenylthiohydantoin / therapeutic use
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Prostatic Neoplasms, Castration-Resistant / blood
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Prostatic Neoplasms, Castration-Resistant / metabolism
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Prostatic Neoplasms, Castration-Resistant / pathology*
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Prostatic Neoplasms, Castration-Resistant / therapy*
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Receptors, Androgen / metabolism
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Receptors, Interleukin / metabolism
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Signal Transduction
Substances
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Androgen Receptor Antagonists
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Androgens
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Benzamides
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Interleukin-23
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Nitriles
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Receptors, Androgen
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Receptors, Interleukin
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Phenylthiohydantoin
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enzalutamide