Calcinotto et al. demonstrated that in human and mouse castration-resistant prostate cancers, polymorphonuclear myeloid-derived suppressor cells are enriched in the tumor microenvironment, where they confer resistance to androgen deprivation therapy (ADT) via secretion of IL-23. IL-23 regulated the pSTAT3-RORγ signaling axis to drive the transcription of the androgen receptor (AR) and its target genes, leading to survival of prostate cancer cells despite androgen deprivation. In mice, anti-IL-23 treatment reversed resistance to ADT and enhanced the efficacy of AR antagonist enzalutamide to decrease tumor volume.
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.
Author Info: (1) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (2) Institute of Oncology Research (IOR), Oncology Institute of South
Author Info: (1) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (2) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (3) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (4) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (5) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (6) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (7) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (8) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (9) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (10) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (11) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. (12) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (13) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (14) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (15) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (16) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (17) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (18) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (19) Department of Urology, University of Padova, Padova, Italy. (20) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (21) Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy. (22) Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy. (23) IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK. (24) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (25) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (26) The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK. (27) Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. andrea.alimonti@ior.iosi.ch. Universita della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland. andrea.alimonti@ior.iosi.ch. Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne, Switzerland. andrea.alimonti@ior.iosi.ch. Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy. andrea.alimonti@ior.iosi.ch.
