# Bioinformatics Screening of Tumor-Derived Neuropeptides Mediating Neuroimmune Axis of Head and Neck Cancer

## TL;DR

This study identifies tumor-secreted neuropeptides that help head and neck cancers grow by linking nerve and immune signals, offering new targets for treatment.

## Contribution

The study introduces tumor-derived neuropeptides as key mediators of neuroimmune crosstalk in head and neck cancer.

## Key findings

- Over half of neuropeptides are expressed in head and neck squamous cell carcinoma (HNSC), with 16% showing differential expression compared to normal tissue.
- Neuropeptides like PTHLH, NMB, GAST, APLN, and LYNX1 are strongly linked to immune checkpoint genes and neurotrophic factors in HNSC.
- Neuropeptide expression differs between patients who respond and those who do not respond to immune checkpoint therapy.

## Abstract

Head and neck cancers advance rapidly by establishing dense nerve networks that not only promote tumor growth but also enable immune evasion. Despite their critical role, the specific molecules driving this nerve–immune communication—and representing promising therapeutic targets—remain largely unidentified. In this study, we hypothesized that tumor-secreted neuropeptides act as pivotal mediators within the neuroimmune axis, orchestrating interactions that facilitate cancer progression and treatment resistance. Through comprehensive analysis of existing data, we identified key neuropeptides strongly associated with factors driving nerve density, suppressed immune activity, and resistance to therapy. These molecules represent promising, targetable “messengers” that link neural and immune pathways within the tumor microenvironment. Our findings lay a crucial foundation for future mechanistic research aimed at disrupting nerve–immune crosstalk, opening new avenues for innovative therapies to improve outcomes for patients battling head and neck cancers.

Background/Objectives: Emerging studies have indicated the importance of intra-tumoral neuronal signals in tumor progression and immune modulation. However, there is limited insight into neuroimmune crosstalk, and the molecules involved are largely unknown. This study investigates the relationship between tumor-derived neuropeptides and immune modulation in head and neck squamous cell carcinoma (HNSC). Methods: By utilizing neuropeptide databases and web tools leveraging TCGA data, neuropeptides’ expression and their associations with neurotrophic factors, immune cell infiltration, and immune checkpoints were analyzed, followed by survival analysis. Results: Over half of the neuropeptides were expressed in HNSC, with 16% exhibiting differential expression compared to normal counterparts. Notably, differentially expressed neuropeptides showed significant correlations with neurotrophic factors, immune cell infiltration, and checkpoint genes. Further, their expression was significantly different in responder and non-responder patient samples subjected to immune checkpoint therapy. Neuropeptide genes—PTHLH, NMB, GAST, APLN, and LYNX1—were identified and emerged as crucial mediators in neuroimmune crosstalk. Additionally, the neurotrophic gene NTRK1 exhibited extensive correlation with immune checkpoint genes, underscoring the prevalence of neuroimmune crosstalk in HNSC. Conclusions: These findings shed light on the role of tumor-derived neuropeptides in neuroimmune regulation in HNSC, offering valuable insights for future studies to decode the cancer neuroscience of HNSC progression and therapy.