Nociceptor Neurons Decrease Cancer Immunosurveillance

Tumor denervation limits cancer growth, but the mechanisms behind this are unknown. We find that malignant melanoma cells interact with pain-initiating nociceptor neurons by increasing neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. In turn, nociceptor-produced neuropeptides increase exhaustion of cytotoxic T cells (PD1+Lag3+Tim3+INFγ-), limiting their capacity to eliminate melanoma cells. Genetic TRPV1 or NaV1.8 lineage ablation, local pharmacological silencing as well as blockade of vesicle release from tumor-innervating nociceptors enhance tumor-infiltrating leukocyte (TIL) numbers and increase survival of mice subject to orthotropic melanoma inoculation, blunting tumor growth and TIL exhaustion. We conclude that reducing neuropeptide release from tumor-innervating nociceptors, by eliminating their immunomodulatory action on cytotoxic CD8 T cell, may be a useful therapeutic intervention to boost immune surveillance.