Sensory Neurotransmitter Calcitonin Gene‐Related Peptide Modulates Tumor Growth and Lymphocyte Infiltration in Oral Squamous Cell Carcinoma

• Published in: Advanced biology Vol. 6; no. 9; pp. e2200019 - n/a
• Main Authors: McIlvried, Lisa A., Atherton, Megan A., Horan, Nicole L., Goch, Tori N., Scheff, Nicole N.
• Format: Journal Article
• Language: English
• Published: Germany 01.09.2022
• Subjects: Animals; Calcitonin Gene-Related Peptide - genetics; calcitonin gene‐related peptide; cancer; Carcinoma, Squamous Cell - drug therapy; CD8-Positive T-Lymphocytes - chemistry; Head and Neck Neoplasms; immune; Mice; Mice, Knockout; Mouth Neoplasms - drug therapy; neurotransmission; Neurotransmitter Agents; oral; Sensory Receptor Cells - chemistry; Squamous Cell Carcinoma of Head and Neck; calcitonin gene-related peptide; cancer; oral; immune; neurotransmission
• ISSN: 2701-0198; 2701-0198
• DOI: 10.1002/adbi.202200019

Head and neck squamous cell carcinoma are highly innervated by peripheral sensory neurons. Local neurotransmitter release (e.g., calcitonin gene‐related peptide (CGRP)) from sensory neurons innervating cancer is linked to tumorigenesis. CGRP‐immunoreactive nerve presence comprised 9.53±1.9% of total nerve area across 11 HNSCC patients. A syngeneic tongue tumor transplant mouse model of oral cancer and a global Calca knockout mouse (CGRPKO) are used to investigate the impact of CGRP signaling on tumor growth and the associated immune response in vivo. In tumor‐bearing CGRPKO mice, there is a significant reduction in tumor size over time compared to wildtype mice using two different mouse oral cancer cell lines. Furthermore, tumor tissue from CGRPKO mice had a significant increase in tumor‐infiltrating CD4+ T cells, cytotoxic CD8+ T cells, and NK1.1+ NK cells compared to wildtype. Fluorescent‐activated cell sorting and real‐time qPCR are used to confirm that CD4+ T cells are isolated from tumor‐bearing wildtype mice containing a high expression of Ramp1 compared to sham mice. These data suggest that sensory neurotransmitter CGRP may modulate oral cancer progression via tumor immunosurveillance. Understanding the relationship between sensory neurons and cancer will aid in repurposing clinically available nervous system drugs for the treatment of cancer. Peripheral nerves can influence the tumor‐associated microenvironment. In oral squamous cell carcinoma, pain is a primary feature and calcitonin gene‐related peptide (CGRP)‐releasing sensory nerves dominate tumor innervation. CGRP signaling drives a pro‐tumor microenvironment by limiting immunosurveillance of cancer. Reducing CGRP release from tumor‐innervating sensory nerves may be a viable therapeutic strategy to reduce pain and slow cancer progression.