# NGF recruits nerve fibers to reprogram an immunosuppressive microenvironment in melanoma

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $469,848

## Abstract

Nerve infiltration has been implicated in the formation and progression of several solid tumor types
including prostate, gastric, and pancreatic cancers. However, despite its neural origin, melanoma
innervation has not been previously reported. In our preliminary studies, we discovered that melanoma
tumor tissues from patient samples and mouse models are highly innervated. This innervation is
dependent on tumor cell expression of nerve growth factor (NGF), as targeted NGF depletion eliminates
intratumoral nerve fibers. Importantly, melanoma denervation via NGF knockdown or chemical
sympathectomy dramatically reduces tumor burdens by remodeling the tumor microenvironment (TME).
This TME reprogramming is associated with increased cytokine and chemokine expression, CD103+ DC
activation, and CD8+ T cell recruitment, suggesting that NGF or nerve-derived neurotransmitters support
tumor growth by suppressing antitumor immunity. Importantly, we confirmed this inverse correlation
between tumor innervation and inflammation using clinical samples: melanomas expressing low levels of
NGF are immunologically hot and associated with improved patient survival. These findings inspire our
central hypothesis that NGF-mediated innervation of the tumor microenvironment can be exploited
pharmacologically to reverse immunosuppression. In this study, we will test this hypothesis with the
following three aims: Aim 1 will dissect molecular mechanisms of NGF-mediated remodeling of the
intratumor immune microenvironment. Aim 2 will dissect molecular mechanisms by which NGF regulates
T cell activation. Aim 3 will determine the pre-clinical efficacy of a therapeutic strategy combining NGF
axis inhibition and immune checkpoint blockade against melanoma. Findings from the proposed studies
will lay the foundation upon which potential combinational therapies can be developed to combat this
disease.

## Key facts

- **NIH application ID:** 10088428
- **Project number:** 5R01CA249726-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Qijing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,848
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088428

## Citation

> US National Institutes of Health, RePORTER application 10088428, NGF recruits nerve fibers to reprogram an immunosuppressive microenvironment in melanoma (5R01CA249726-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10088428. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*