Nociceptor neurons affect cancer immunosurveillance

Area of Science:

• Immunology
• Neuroscience
• Oncology

Background:

• Solid tumors are innervated by sensory and autonomic nerve fibers.
• The impact of tumor innervation by pain-sensing neurons on cancer immunosurveillance is not well understood.

Purpose of the Study:

• To investigate the interaction between melanoma cells and nociceptor neurons.
• To determine if neuropeptides released by nociceptors affect anti-tumor immunity.

Main Methods:

• Studied melanoma cell interaction with nociceptor neurons.
• Investigated the effect of Calcitonin gene-related peptide (CGRP) on cytotoxic CD8+ T cells.
• Utilized genetic ablation of TRPV1 lineage, pharmacological silencing of nociceptors, and CGRP receptor antagonism in mouse models.
• Performed single-cell RNA sequencing on human melanoma patient biopsies.

Main Results:

• Melanoma cells promote nociceptor neurite outgrowth and neuropeptide release.
• CGRP directly increases exhaustion of cytotoxic CD8+ T cells, impairing melanoma elimination.
• Blocking CGRP signaling or sensory nerves reduced T cell exhaustion, decreased tumor growth, and significantly improved mouse survival.
• Human melanoma data showed RAMP1+ CD8+ T cells were more exhausted, correlating with poorer prognosis.

Conclusions:

• Tumor-innervating nociceptors release CGRP, which suppresses anti-tumor CD8+ T cell responses.
• Targeting CGRP signaling represents a potential strategy to enhance cancer immunosurveillance and improve therapeutic outcomes in melanoma.