Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer.
Falquet M., El Ahanidi H., Gomez-Cadena A., Su Z., Cornu A., Wyss T., Kizil B., Pick R., Falamaki K., Wirapati P., Fiordi B., Senoner I., Maresca DC., Kallal N., Guedj D., Kreutzfeldt M., Tille J-C., Leblond MM., Michaud K., Pesce S., Candiani S., Golebski K., Dagher J., Charrier M., Pressacco Brossier C., Grobet-Jeandin E., Marone R., Hugues S., Jeker LT., Verdeil G., Merkler D., Marcenaro E., Scheiermann C., Attaleb M., Benamran D., Tsantoulis P., Ercolano G., Trabanelli S., Jandus C.
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.