Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer
Abstract
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.
Article Details
Authors (39)
Maryline Falquet
Hajar El Ahanidi
Alejandra Gomez-Cadena
Ziyang Su
Anthony Cornu
Tania Wyss
Burak Kizil
Robert Pick
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva
Katayoun Falamaki
Pratyaksha Wirapati
Benedetta Fiordi
Isis Senoner
Daniela Claudia Maresca
Neil Kallal
Danaé Guedj
Mario Kreutzfeldt
Jean-Christophe Tille
Marine M. Leblond
Katarzyna Michaud
Silvia Pesce
Simona Candiani
Korneliusz Golebski
Julien Dagher
Melinda Charrier
Caroline Pressacco Brossier
Elisabeth Grobet-Jeandin
Romina Marone
Stéphanie Hugues
Lukas T. Jeker
Grégory Verdeil
Doron Merkler
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva
Emanuela Marcenaro
Christoph Scheiermann
Mohammed Attaleb
Daniel Benamran
Petros Tsantoulis
Giuseppe Ercolano
Sara Trabanelli
Camilla Jandus