IL-23 from Myeloid Cells Fuels the Flames in Prostate Cancer
Nancy Mize Gonzalez
Introduction: Prostate cancer (PC), the most common malignancy in men, kills over 30,000 men each year in the US.1,2 Chemical castration, first-line therapy, weakens pathological androgen signaling, but often fails to prevent recurrence, granting mean survival of just 9-36 months in conjunction with chemotherapy.3,4,5,8 Post-castration, PC may become androgen-independent, or may develop heightened androgen-sensitivity, associated with amplifications in the AR gene.1,2,3,4,5 Constitutive AR activity induces cell proliferation and halts apoptosis, driving tumorigenesis.1,2 In the absence of AR signaling, STAT3-RORy signaling can amplify pathways downstream of AR.1,4,5,6,10 IL-23, a pro-inflammatory member of the IL-12 cytokine family, can be produced by myeloid-derived suppressor cells (MDSCs), favoring an immunosuppressive tumor microenvironment.5,6,9 Further, IL-23 can promote STAT3-RORy signaling, potentially driving AR sensitivity mechanisms.1,4,5,6,9,10 IL-23 can also contribute to the tumor microenvironment by polarizing T cells into inflammatory TH17s, which secrete IL-4, further recruiting and expanding MDSCs.4 The number of tumor MDSCs directly correlates with increasing mortality in PC patients.4,5,9 Interrupting pathological immune signaling in PC could promote castration sensitivity and prevent tumor evasion. Methods & Results: Calcinotto et al. analyzed biopsies from PC patients, both castration-sensitive and castration-resistant, comparing PMN-MDSCs (CD11b+CD33+CD15+). In castration-resistant prostate cancer (CRPC), the MDSCs expanded, clustering near EpCAM+ epithelial tumor cells. Hypothesizing that MDSCs directly participate in CRPC pathogenesis, they created a conditional knockout model (PtenPC-/-) which develops PC due to loss of Pten. Tumors regressed initially following surgical castration of PtenPC-/- mice, but after 4 weeks began to re-emerge as CRPC. AR target genes remained downregulated during the castration sensitive phase, only to become upregulated in CRPC. In a temporal recruitment study, PMN-MDSCs increased over time in parallel to CRPC emergence. To test if MDSC depletion could prevent CRPC emergence, Calcinatto et al. irradiated and then reconstituted bone marrow of sham or castrated PtenPC-/- mice with either BM precursors from Il23aWT or IL23aKO mice, but without T, B, or Natural Killer cells. Mice without myeloid IL23 (PtenPC-/-IL23KO) showed dramatic reduction in tumor volume and number of proliferating cells, with a downregulation in AR target genes, versus PtenPC-/-IL23WT mice. Conclusions: These exciting data from Calcinatto et al. offer compelling insight into tumor escape mechanisms and treatment failure in CRPC.5 IL23 blockade, already clinically used for autoimmune disease,5,12 may provide effective treatment and hope for patients with CRPC.
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