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.

No abstract

Tumour cells promote the expansion and intra-tumoural recruitment of Myeloid-derived suppressor cells (MDSCs), a subset of immature myeloid cells, that support tumour cell proliferation and confer treatment resistance. While immature myeloid cells have a very short lifespan, whether pathogenic MDSCs can persist in the tumour microenvironment remains unknown. Here, we report the identification of a subset of long-lasting MDSCs that upregulate markers of cellular senescence and the TREM2 receptor. Senescent-like MDSCs possess higher pro-inflammatory capabilities compared to canonical MDSCs. Genetic and pharmacological elimination of senescent-like MDSCs decreases tumour progression in different mouse models of prostate cancer. Mechanistically, we find that Apolipoprotein E (ApoE) secreted by prostate tumour cells binds TREM2 in senescent-like MDSCs, thereby regulating the survival of these cells. ApoE and TREM2 mRNA levels are upregulated in prostate cancers and correlate with poor patients’ prognosis. Taken together, these results reveal a novel mechanism by which the tumour microenvironment shapes the intra-tumoural immune response. Pathogenic senescent-like MDSCs persist longer in the tumour microenvironment and can be eliminated by histone deacetylase inhibitors enhancing the efficacy of standard therapy in prostate cancer.