Neuromedin U: A New Way Neuroendocrine Prostate Cancer May Hide From the Immune System

Neuroendocrine prostate cancer is one of the most aggressive forms of the disease and remains particularly difficult to treat. A new Oncogene study has identified a possible mechanism that helps these tumours suppress the immune response, centred on a molecule called Neuromedin U, or NMU.

In mouse models of neuroendocrine prostate cancer, the researchers found that early tumour development was accompanied by an increase in neutrophils that suppress immune activity and a reduction in CD8+ T cells, the immune cells that can directly attack cancer. At the same time, NMU emerged as one of the most strongly increased neuronal signalling molecules.

The same pattern also appeared in human samples. NMU was highly expressed in prostate cancer and was particularly associated with AR-negative, neuroendocrine-positive metastases, suggesting that it may become especially important as tumours move away from conventional androgen-receptor-driven biology.

The researchers then showed how the pathway may work. NMU stimulated neutrophils to migrate and produce S100A9, a molecule involved in inflammation and immune suppression. These cells were then able to reduce T-cell proliferation, effectively helping the tumour create a more protected environment around itself.

The most interesting result came from blocking the NMU/S100A9 pathway. Genetic or pharmacological inhibition slowed neuroendocrine prostate cancer growth in preclinical models and allowed more tumour-specific CD8+ T cells to enter the tumour. It also improved the activity of immune checkpoint therapy, a treatment that has generally shown limited effectiveness in unselected prostate cancer.

This raises an intriguing possibility: rather than trying to make immunotherapy stronger on its own, it may be necessary first to remove some of the mechanisms that keep immune cells out of neuroendocrine prostate tumours. The NMU/S100A9 axis could become a therapeutic target in a disease that currently has very few effective options.

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