Serotonin signaling linked to suppressed anti-tumor immunity in lung neuroendocrine cancer

From serotonin through macrophages to T cells

Researchers from the National Cancer Center, Kyoto University, Nagoya University, Kindai University and the Cancer Institute reported that cancers with high DLL3 expression also showed high expression of the serotonin-synthesis enzyme TPH1 and more immunosuppressive macrophages. They reported that tumor-produced serotonin acts on HTR7-expressing macrophages to suppress CD8-positive T-cell function.

In cases where DLL3 was expressed, the reason immunotherapy did not always produce sufficient effects had not been clear, according to the research announcement.

The reported work connects serotonin produced by lung neuroendocrine cancer cells with HTR7-positive macrophages and suppressed CD8-positive T-cell function. In mouse experiments, genetically or pharmacologically inhibiting cancer-cell serotonin production or macrophage HTR7 increased immunotherapy effects.

The finding offers a reported explanation for why some DLL3-expressing lung neuroendocrine cancers may respond insufficiently to immunotherapy. The treatment-related results remain preclinical: they were described in cell and mouse experiments, not as a demonstrated clinical treatment.