OPIOID-EXPRESSING B CELLS SILENCE TUMOR-INFILTRATING NOCICEPTOR NEURONS

Area of Science:

• Neuroscience
• Immunology
• Oncology

Background:

• Nociceptor neurons transmit pain signals and modulate immunity via neuropeptides.
• Tumor-innervating nociceptors release calcitonin gene-related peptide (CGRP), interacting with receptor activity-modifying protein 1 (RAMP1) in head and neck squamous cell carcinoma (HNSCC) and melanoma.
• Opioid use in HNSCC correlates with increased pain, perineural invasion, and decreased B-cell infiltration, suggesting poorer survival.

Purpose of the Study:

• To investigate the role of nociceptors, B cells, and their signaling pathways in cancer immunity and pain.
• To explore the therapeutic potential of targeting nociceptin/orphanin FQ (N/OFQ) and RAMP1 pathways in cancer treatment and pain management.

Main Methods:

• Retrospective analysis of HNSCC patient clinical charts.
• In silico single-cell RNA sequencing of HNSCC tumors.
• Mouse models of oral squamous cell carcinoma (oSCC) and melanoma.
• Pharmacological blockade and activation of specific signaling pathways (OPRL1, RAMP1).
• B-cell depletion studies.

Main Results:

• Opioid use downregulates N/OFQ in HNSCC; B cells are a primary source of N/OFQ.
• High expression of Pnoc or Oprl1 correlates with better survival in melanoma and HNSCC.
• Blocking OPRL1 reduced cancer-induced pain; activating OPRL1 reduced tumor size and enhanced T-cell infiltration.
• B-cell depletion or OPRL1 blockade increased tumor growth and exacerbated pain.
• RAMP1+ B cells express Pnoc, suppressed by CGRP; blocking RAMP1 promoted Pnoc expression and reduced tumor growth.

Conclusions:

• The N/OFQ and RAMP1 pathways are critical regulators of anti-tumor immunity and cancer pain.
• Targeting these pathways offers a dual therapeutic strategy to enhance anti-tumor responses and alleviate pain in HNSCC and melanoma.