Tumor-innervating neurons modulate anti-cancer immunity

• Applicant: Dr. Laura Brabenec
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542462899

Tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems, which are directly involved in immune responses. Cancer cells actively modulate these responses by tweaking the transcriptome of tumor-innervating neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release, to blunt anti-tumor immunity and ensure tumor progression and survival. Calcitonin gene-related peptide (CGRP) - one such nociceptor-produced neuropeptide binding to RAMP1 - directly increases the exhaustion of immune cells, which limits their capacity to eliminate melanoma. The role of CGRP-releasing sensory neurons and the impact of the CGRP-RAMP1 axis on tumor development have been unraveled so far, and elucidation of the crosstalk between cancer cells, leukocytes, nociceptors, and neuropeptides could offer novel targets for therapeutic approaches in anti-tumor-therapy. With this respect, we aim to test whether: 1. Melanoma-innervating neurons-released CGRP shape dendritic cells (DCs) anti-tumor immunity. 2. Rimegepant can safeguard anti-tumor immunity in melanoma patient-derived xenografted mice. 3. Tumor-innervating neurons sense gut dysbiosis, which impacts responsiveness to immunotherapy (checkpoint blockers). 4. Spatially resolved transcriptomics can reveal how sensory neurons impact DC function. These aims should unravel a novel view of tumor-innervating neurons and their ability to promote tumor growth and modulate anti-tumor responses. The elucidation of neuron-tumor crosstalk could offer further insights into crucial pathways that provide novel therapeutic approaches for cancer treatment. Specifically, we want to elucidate whether a local anesthetic blocking sensory neurons (QX-314) or repurposing Rimegepant, FDA-approved migraine medication and potent RAMP1 inhibitor, beneficially influence anti-tumor responses. This study may reveal that tumor neoinnervation is as crucial as neo-angiogenesis in tumor progression and development.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professor Dr. Sebastien Talbot