Neuromedin U 'innervation' reprograms myeloid immunosuppression in neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an increasingly recognized, highly aggressive disease variant with no actionable therapeutic targets and a life expectancy of 7 months or less. Using a transgenic mouse model, we now show that early stages of NEPC are associated with increased intraprostatic recruitment of Ly6G⁺ polymorphonuclear neutrophils (PMN) and reduced infiltration of CD8⁺ T cells. This coincided with expansive transcriptional changes of increased cell viability and cell migration, as well as upregulation of multiple neuronal mediators with the neuropeptide, Neuromedin U (NMU) as the top hit (Z score = 4.34; FDR < 5%; p = 3.62 × 10^-9). Analysis of a large cohort of human patient samples revealed that NMU was highly expressed in early and late stage prostate cancer, preferentially segregating with AR^-/NE⁺ metastases. Exposure of PMN to recombinant NMU was sufficient to stimulate cell migration, inflammatory gene expression with increased levels of the cytokine-like alarmin, S100A9 and suppression of T cell proliferation. Genetic or pharmacological targeting of NMU/S100A9 signaling inhibited NEPC growth, reinvigorated an intratumoral immune microenvironment via recruitment of tumor antigen-specific CD8⁺ T cells with 'stem-like' (TCF1⁺/PD1⁺) and cytotoxic (GrzB⁺/KLRG1⁺) properties and enhanced the activity of therapeutic immune checkpoint inhibition, in vivo. Therefore, NMU 'innervation' drives myeloid immunosuppression in NEPC and provides a therapeutic target to restore sensitivity to immunotherapy in this highly refractory malignancy.