Nociceptor neurons affect cancer immunosurveillance.

Autor: Balood M; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada.; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, Quebec, Canada., Ahmadi M; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Eichwald T; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada.; Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Ahmadi A; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Majdoubi A; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Quebec, Canada., Roversi K; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Roversi K; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Lucido CT; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Restaino AC; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Huang S; Cygnal Therapeutics, Cambridge, MA, USA., Ji L; Cygnal Therapeutics, Cambridge, MA, USA., Huang KC; Cygnal Therapeutics, Cambridge, MA, USA., Semerena E; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Thomas SC; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Trevino AE; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Merrison H; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Parrin A; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Doyle B; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Vermeer DW; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Spanos WC; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Williamson CS; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Seehus CR; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Foster SL; Depression Clinical Research Program, Massachusetts General Hospital, Boston, MA, USA., Dai H; Cygnal Therapeutics, Cambridge, MA, USA., Shu CJ; Cygnal Therapeutics, Cambridge, MA, USA., Rangachari M; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, Quebec, Canada., Thibodeau J; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Quebec, Canada., V Del Rincon S; Department of Oncology, McGill University, Montréal, Quebec, Canada., Drapkin R; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Rafei M; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada., Ghasemlou N; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada., Vermeer PD; Cancer Biology and Immunotherapies, Sanford Research, Sioux Falls, SD, USA., Woolf CJ; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA., Talbot S; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Quebec, Canada. sebastien.talbot@queensu.ca.; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. sebastien.talbot@queensu.ca.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Nov; Vol. 611 (7935), pp. 405-412. Date of Electronic Publication: 2022 Nov 02.
DOI: 10.1038/s41586-022-05374-w
Abstrakt: Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems 1-5 . 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: