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.
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Data availability
The RNAseq data of human ILC2s generated in this study have been deposited in NCBI’s Gene Expression Omnibus database under the GEO accession number GSE311046. The TCGA Bladder Urothelial Carcinoma (BLCA) RNA sequencing dataset is available from the National Institutes of Health’s (NIH) dbGaP (Database of Genotypes and Phenotypes) database under accession number phs000178 [https://portal.gdc.cancer.gov/projects/TCGA-BLCA]. Microarray gene expression datasets are available from the National Center for Biotechnology Information (NCBI)‘s GEO database under accession numbers GSE31684 and GSE48075. - Human ILCs: ArrayExpress accession E-MTAB-8494 (bulk RNA sequencing data) [https://www.ebi.ac.uk/biostudies/ArrayExpress/studies/E-MTAB-8494], GSE112591 (bulk RNA sequencing data) [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112591], GSE150050 (single-cell RNA sequencing, Smart-Seq2 protocol) [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE150050] The remaining data are available within the article, Supplementary information or Source Data file and/or from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
We thank patients and healthy donors for participating in this study. We thank the genomic and flow cytometry facilities of the Universities of Lausanne and Geneva for their excellent technical assistance. We thank Prof Tim Halim (University of Cambridge, CRUK Cambridge Institute, Cambridge, UK) for the insightful discussions on the project and Prof Andrew Mackenzie (MRC Laboratory of molecule biology, Cambridge, UK) for providing the ILC2KO animals. We thank Nataniele Piol (MD), Anatomia Patologica Universitaria, IRCCS Ospedale Policlinico San Martino, Genova, Italy who kindly provided us some of the bladder cancer patient sections. This work was supported by the Ludwig Institute for Cancer Research, by grants from Swiss National Science Foundation (PRIMA PR00P3_179727), the IDEAL grant from Debiopharm, the INNOGap grant from UNIGE, a generous donor, advised by Carigest SA to C.J., the Fond’Action contre le cancer grant to H.E.A., AIRC grant (Fondazione AIRC IG 2021, Id. 26037) to E.M. and AIRC grant (Fondazione AIRC MFAG 2021, Id. 26002) to G.E., the Swiss Cancer League (KLS-4836-08-2019) to C.S., the Geneva Cancer League (2106) to C.S., the EU ITN (813284, INTEGRATA) to C.S., and the Swiss National Science Foundation MD-PhD fellowship to D.G.; B.F is supported by a PhD fellowship from the ISREC Foundation. L.T.J. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 818806).
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M.F., G.E., S.T. and C.J. conceived the project. M.F., H.E.A., A.G-C., Z.S., A.C., T.W., B.K., R.P., K.F., P.W., B.F., I.S., N.K., D.G., D.C.M., S.P., S.C., G.E., S.T. and C.J. performed experiments and data analyses. M.K., R.M., S.H., L.J., E.M., C.S. and P.T. assisted in data analyses and interpretation. J-C.T., M.M.L., K.M., K.G., J.D., M.C., C.P.B., E.G-J., G.V., D.M., M.A. and D.B. provided study material. M.F., G.E., S.T. and C.J. wrote the manuscript. All authors interpreted the data and contributed valuable feedback for the improvement of the manuscript.
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L.T.J. co-founder, holding equity of Cimeio Therapeutics AG (Cimeio). Cimeio board member. Sponsored research agreement with Cimeio. Inventor on granted patents and patent applications related to immune cell engineering and antibodies. Received speaker fees from Novartis. Paid consultant for Kyowa Kirin. No competing interests directly affecting this study. The other authors declare no conflicts of interest.
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Falquet, M., El Ahanidi, H., Gomez-Cadena, A. et al. Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69841-y
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DOI: https://doi.org/10.1038/s41467-026-69841-y
