Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer
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<sup>+</sup> ILC2s might represent a targetable strategy to improve survival, particularly in ICB-resistant patients.
Authors
- Mohammed ATTALEB
- Alejandra Gomez‐Cadena (ORCID: https://orcid.org/0000-0002-4888-3362)
- Élisabeth Grobet-Jeandin (ORCID: https://orcid.org/0000-0003-4602-8351)
- Silvia Pesce (ORCID: https://orcid.org/0000-0002-9798-4944)
- Isis Senoner
- Christoph Scheiermann (ORCID: https://orcid.org/0000-0002-9212-0995)
- Benedetta Fiordi (ORCID: https://orcid.org/0000-0002-7555-2040)
- Katayoun Falamaki
- Lukas T. Jeker (ORCID: https://orcid.org/0000-0002-3359-8796)
- Sara Trabanelli (ORCID: https://orcid.org/0000-0001-8648-1324)
- Simona Candiani (ORCID: https://orcid.org/0000-0002-4453-5475)
- Grégory Verdeil (ORCID: https://orcid.org/0000-0001-9445-8474)
- Ziyang Su
- M.M. Leblond (ORCID: https://orcid.org/0009-0007-6919-2855)
- Giuseppe Ercolano (ORCID: https://orcid.org/0000-0001-6026-2588)
- Daniela Claudia Maresca
- Emanuela Marcenaro (ORCID: https://orcid.org/0000-0003-4103-7566)
- Mario Kreutzfeldt (ORCID: https://orcid.org/0000-0003-0335-2733)
- Camilla Jandus (ORCID: https://orcid.org/0000-0002-7405-5747)
- Robert Pick (ORCID: https://orcid.org/0000-0001-9785-8481)
- Pratyaksha Wirapati (ORCID: https://orcid.org/0000-0002-0327-4686)
- Maryline Falquet (ORCID: https://orcid.org/0000-0002-5940-8583)
- Doron Merkler (ORCID: https://orcid.org/0000-0002-0247-2007)
- Julien Dagher (ORCID: https://orcid.org/0000-0003-3864-5149)
- Burak Kizil (ORCID: https://orcid.org/0000-0003-2348-1305)
- Petros Tsantoulis (ORCID: https://orcid.org/0000-0003-3613-6682)
- Romina Marone (ORCID: https://orcid.org/0000-0003-1474-1689)
- Neil Kallal
- Caroline Brossier
- Anthony Cornu
- Korneliusz Golebski
- Tania Wyss
- Daniel Benamran
- Melinda Charrier
- Katarzyna Michaud
- Hajar El Ahanidi
- Stéphanie Hugues
- Danaé Guedj
Institutions
- University of Geneva (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Basel (CH)
- University Hospital of Basel (CH)
- University of Oxford (GB)
- National Centre for Nuclear Energy, Science and Technology (MA)
- University Hospital of Geneva (CH)
- Translational Research in Oncology (FR)
- Ludwig Cancer Research (CH)
- University Centre of Legal Medicine (CH)
- Azienda Ospedale - Università Padova (IT)
- Amsterdam University Medical Centers (NL)
- University of Naples Federico II (IT)
- University of Genoa (IT)
- University of Amsterdam (NL)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-21
- DOI
- https://doi.org/10.1038/s41467-026-69841-y
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00