# Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer

## TL;DR

Mast cells produce nerve growth factor (NGF), which activates ILC2s to promote bladder cancer growth and reduce survival.

## Contribution

Identifies NGF as a driver of ILC2 pro-tumoral functions and suggests TrkA inhibition as a potential treatment strategy.

## Key findings

- ILC2s express the NGF receptor TrkA and respond to NGF by secreting type-2 cytokines.
- NGF-producing mast cells activate ILC2s to induce regulatory T cells, promoting tumor growth.
- Blocking TrkA improves survival and response to immune checkpoint blockade in bladder cancer models.

## Abstract

Innate lymphoid cells type 2 (ILC2s) are key regulators of tissue homeostasis and inflammation. In cancer, ILC2s can exhibit pro-tumoral functions by increasing the myeloid derived suppressor cells (MDSC)/T-cell ratio. Nevertheless, the upstream ILC2 triggers remain poorly defined. Here, we identify nerve growth factor (NGF) as the driver of ILC2 pro-tumoral functions in patients with bladder cancer. We show that ILC2s express the NGF receptor TrkA and respond to NGF by secreting type-2 cytokines. In the tumor microenvironment, NGF-producing mast cells accumulate and activate ILC2s to induce regulatory T cells (Tregs), ultimately fostering tumor growth. In patients, NGF levels inversely correlate with survival in ILC2-rich tumors, underscoring the clinical significance of this axis. In vivo administration of a selective TrkA inhibitor improves survival in orthotopic tumor-bearing female mice and sensitizes them to immune checkpoint blockade (ICB). Overall, we identify NGF as an ILC2 activator that shapes pro-tumoral ILC2 functions. The blockade of TrkA+ ILC2s might represent a targetable strategy to improve survival, particularly in ICB-resistant patients.

Neurotrophic factor Nerve Growth Factor (NGF) is involved in bladder physiopathology. Here the authors report that mast-cell derived NGF sustains the pro-tumoral functions of ILC2s in bladder cancer (BC), showing that selective targeting of the NGF receptor TrkA improves survival and response to immune checkpoint blockade in BC models.