IL23 Produced by MDSCs Promotes Castration-Resistant Prostate Cancer

Many patients with prostate cancer develop resistance to androgen-deprivation therapy and progress to an aggressive castration-resistant prostate cancer (CRPC). These patients have a poor prognosis and often have activation of androgen receptor (AR) signaling via alternative pathways, but the mechanisms underlying castration resistance remain poorly understood. Calcinotto and colleagues sought to understand the role of the tumor microenvironment in CRPC progression. Analysis of biopsies from patients with CRPC compared with castration-sensitive prostate cancer (CSPC) revealed that CRPCs had an enrichment of poly-morphonuclear myeloid-derived suppressor cells (PMN-MDSC). In mouse models of CRPC, PMN-MDSC infiltration was linked to AR activation, and thereby conferred castration resistance. Treatment with a CXCR2 antagonist reduced PMN-MDSC infiltration and delayed the progression to CRPC. Tumor-infiltrating MDSCs secreted IL23, which induced transcription of AR target genes, conferred resistance to androgen deprivation and promoted prostate cancer cell proliferation and survival. Accordingly, IL23 was expressed in PMN-MDSCs from biopsies from patients with CRPC, plasma IL23 levels were higher in patients with CRPC than patients with CSPC, and patients with CRPC had elevated mRNA levels of IL23A and IL23R. Mechanistically, IL23 released by MDSCs into the tumor microenvironment activated phoshpo-STAT3–RORγ signaling to drive AR transcription. Consistent with these findings, targeting IL23 with antibody blockade reversed castration resistance in a mouse model of prostate cancer, conferring sensitivity to the AR antagonist enzalutamide and reducing tumor growth. In addition to elucidating a mechanism by which MDSCs in the tumor microenvironment can promote CRPC, these findings suggest the potential for therapeutic targeting of IL23 to restore sensitivity to androgen deprivation in patients with CRPC.

Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 2018 Jun 27 [Epub ahead of print].

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