Nociceptor neurons affect cancer immunosurveillance

Mohammad Balood, Maryam Ahmadi, Tuany Eichwald, Ali Ahmadi, Abdelilah Majdoubi, Karine Roversi, Katiane Roversi, Christopher T. Lucido, Anthony C. Restaino, Siyi Huang, Lexiang Ji, Kai-Chih Huang, Elise Semerena, Sini C. Thomas, Alexandro E. Trevino, Hannah Merrison, Alexandre Parrin, Benjamin Doyle, Daniel W. Vermeer, William C. Spanos, Caitlin S. Williamson, Corey R. Seehus, Simmie L. Foster, Hongyue Dai, Chengyi J. Shu, Manu Rangachari, Jacques Thibodeau, Sonia Rincon, Ronny Drapkin, Moutih Rafei, Nader Ghasemlou, Paola D. Vermeer, Clifford J. Woolf and Sebastien Talbot ()
Additional contact information
Mohammad Balood: Université de Montréal
Maryam Ahmadi: Université de Montréal
Tuany Eichwald: Université de Montréal
Ali Ahmadi: Université de Montréal
Abdelilah Majdoubi: Université de Montréal
Karine Roversi: Université de Montréal
Katiane Roversi: Université de Montréal
Christopher T. Lucido: Sanford Research
Anthony C. Restaino: Sanford Research
Siyi Huang: Cygnal Therapeutics
Lexiang Ji: Cygnal Therapeutics
Kai-Chih Huang: Cygnal Therapeutics
Elise Semerena: Université de Montréal
Sini C. Thomas: Université de Montréal
Alexandro E. Trevino: Boston Children’s Hospital
Hannah Merrison: Boston Children’s Hospital
Alexandre Parrin: Boston Children’s Hospital
Benjamin Doyle: Boston Children’s Hospital
Daniel W. Vermeer: Sanford Research
William C. Spanos: Sanford Research
Caitlin S. Williamson: Sanford Research
Corey R. Seehus: Boston Children’s Hospital
Simmie L. Foster: Massachusetts General Hospital
Hongyue Dai: Cygnal Therapeutics
Chengyi J. Shu: Cygnal Therapeutics
Manu Rangachari: Université Laval
Jacques Thibodeau: Université de Montréal
Sonia Rincon: McGill University
Ronny Drapkin: Perelman School of Medicine, University of Pennsylvania
Moutih Rafei: Université de Montréal
Nader Ghasemlou: Queen’s University
Paola D. Vermeer: Sanford Research
Clifford J. Woolf: Boston Children’s Hospital
Sebastien Talbot: Université de Montréal

Nature, 2022, vol. 611, issue 7935, 405-412

Abstract: Abstract Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1–5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)—one such nociceptor-produced neuropeptide—directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1−/− CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.

Date: 2022
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DOI: 10.1038/s41586-022-05374-w

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