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.
Balood, Mohammad and Ahmadi, Maryam and Majdoubi, Abdelilah and Eichwald, Tuany and Merrison, Hannah and Parrin, Alexandre and Doyle, Benjamin and Vermeer, Daniel and Wang, Chih-Chieh and Thanawala, Monica and Roversi, Katiane and Thomas, Sini C. and Seehus, Corey R. and Foster, Simmie L. and Latini, Alexandra and Rafei, Moutih and Rangachari, Manu and Rincon, Sonia Del and Shu, Chengyi J. and Drapkin, Ronny and Thibodeau, Jacques and Woolf, Clifford J. and Vermeer, Paola D. and Talbot, Sebastien, Nociceptor Neurons Decrease Cancer Immunosurveillance. Available at SSRN: https://ssrn.com/abstract=3571293 or http://dx.doi.org/10.2139/ssrn.3571293
This version of the paper has not been formally peer reviewed.
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