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

Article Article scientifique Article Mast-cell derived nerve growth factor drives ILC2 pro-tumoral functions in bladder cancer eng 2026-02-21 2026-02-21 author Falquet Maryline 0000-0002-5940-8583 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 932439 author El Ahanidi Hajar Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 948569 Département de pathologie et immunologie (PATIM) author Gomez Cadena Alejandra 0000-0002-4888-3362 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 934607 Département de pathologie et immunologie (PATIM) author Su Ziyang Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 402588 Département de pathologie et immunologie (PATIM) author Cornu Anthony 0009-0005-2477-0020 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland.,Human Islet Isolation Facility, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. 682934 author Wyss Lozano Hoyos Tania 0000-0003-2641-0895 Translational Data Science Facility, AGORA Cancer Research Center, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. 939669 author Kizil Burak 0000-0003-2348-1305 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 931539 author Pick Robert 0000-0001-9785-8481 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 921203 Département de pathologie et immunologie (PATIM) author Falamaki Katayoun Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 856560 author Wirapati Pratyaksha 0000-0002-0327-4686 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 982767 author Fiordi Benedetta Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 977693 Département de pathologie et immunologie (PATIM) author Senoner Isis Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 781453 Département des neurosciences cliniques (OTONO) author Maresca Daniela Claudia 0009-0008-4221-6375 Department of Pharmacy, University Federico II of Naples Italy, Naples, Italy. author Kallal Neïl 0009-0001-4299-2699 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 983900 Département de pathologie et immunologie (PATIM) author Guedj Danae 0009-0004-2539-6432 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 778102 Département de pathologie et immunologie (PATIM) author Kreutzfeldt Mario 0000-0003-0335-2733 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Diagnostics, Division of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland. 736806 Département de pathologie et immunologie (PATIM) author Tille Jean-Christophe Department of Diagnostics, Division of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland. 87627 author Leblond Marine M Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. author Michaud Katarzyna University Centre of Legal Medicine Lausanne-Geneva, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland. author Pesce Silvia Department of Experimental Medicine, University of Genova, Genova, Italy.,RCCS Azienda Ospedaliera Metropolitana, Genova, Italy. author Candiani Simona RCCS Azienda Ospedaliera Metropolitana, Genova, Italy.,Department of Earth, Environment and Life Sciences, University of Genova, Genova, Italy. author Golebski Korneliusz Department of Otorhinolaryngology and Head and Neck Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. author Dagher Julien Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Charrier Melinda Department of Oncology, Precision Oncology Service, University Hospital of Geneva, Geneva, Switzerland. 938395 author Pressacco Brossier Caroline Division of Urology, Geneva University Hospitals, Geneva, Switzerland. 742780 author Grobet-Jeandin Elisabeth 0000-0003-4602-8351 Division of Urology, Geneva University Hospitals, Geneva, Switzerland. 718092 author Marone Romina 0000-0003-1474-1689 Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland.,Transplantation Immunology & Nephrology, Basel University Hospital, Basel, Switzerland. author Hugues Stéphanie Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 663452 Département de pathologie et immunologie (PATIM) author Jeker Lukas T 0000-0002-3359-8796 Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland.,Transplantation Immunology & Nephrology, Basel University Hospital, Basel, Switzerland. author Verdeil Grégory 0000-0001-9445-8474 Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. author Merkler Doron 0000-0002-0247-2007 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 735735 Département de pathologie et immunologie (PATIM) author Marcenaro Emanuela 0000-0003-4103-7566 Department of Experimental Medicine, University of Genova, Genova, Italy.,RCCS Azienda Ospedaliera Metropolitana, Genova, Italy. author Scheiermann Christoph 0000-0002-9212-0995 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 891044 Département de pathologie et immunologie (PATIM) author Attaleb Mohammed Centre National de l'Energie, des Sciences et Techniques nucléaires (CNESTEN), Rabat, Morocco. author Benamran Daniel Alexandre Israel Division of Urology, Geneva University Hospitals, Geneva, Switzerland. 618957 Département de chirurgie (CHIRU) author Tsantoulis Petros 0000-0003-3613-6682 Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland.,Translational Data Science Facility, AGORA Cancer Research Center, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Department of Oncology, Precision Oncology Service, University Hospital of Geneva, Geneva, Switzerland. 861166 Département de médecine (DEMED) author Ercolano Giuseppe 0000-0001-6026-2588 Department of Pharmacy, University Federico II of Naples Italy, Naples, Italy. 932440 author Trabanelli Sara 0000-0001-8648-1324 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.,Geneva Center for Inflammation Research, Geneva, Switzerland.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. 932754 Département de pathologie et immunologie (PATIM) author Jandus Camilla 0000-0002-7405-5747 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Camilla.jandus@unige.ch.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland. Camilla.jandus@unige.ch.,Geneva Center for Inflammation Research, Geneva, Switzerland. Camilla.jandus@unige.ch.,Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland. Camilla.jandus@unige.ch.,Translational Research Centre in Onco-Hematology (CRTOH), Geneva, Switzerland. Camilla.jandus@unige.ch. 932821 Département de pathologie et immunologie (PATIM) 3061 10.1038/s41467-026-69841-y 41723132 2041-1723 PMC13039139 https://www.nature.com/articles/s41467-026-69841-y 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. Animals Cell Line, Tumor Cytokines / metabolism Female Humans Immune Checkpoint Inhibitors / pharmacology Immunity, Innate Lymphocytes / immunology Lymphocytes / metabolism Male Mast Cells / immunology Mast Cells / metabolism Mice Mice, Inbred C57BL Nerve Growth Factor / immunology Nerve Growth Factor / metabolism Receptor, trkA / antagonists & inhibitors Receptor, trkA / metabolism T-Lymphocytes, Regulatory / immunology Tumor Microenvironment / immunology Urinary Bladder Neoplasms / drug therapy Urinary Bladder Neoplasms / immunology Urinary Bladder Neoplasms / metabolism Urinary Bladder Neoplasms / pathology Dewey 610 Dewey 616.07 Dewey 616 Dewey 590 Swiss National Science Foundation ILC2 functional manipulation at the single cell level for innovative cancer immunotherapy 179727 CH European Commission Therapeutic Allele Engineering: A novel technology for cell therapy 818806 TALE EU H2020 4f7589ed-e44d-4850-a4d8-b0c1eccdfe48 Centre de recherche translationnelle en onco-hématologie 209 137 Département de pathologie et immunologie 21F 23 Institut de génétique et de génomique 0DH 56 Département de médecine 221 false 1309 Ciblage des lymphocytes sécrétant des cytokines 1015 0a6434c9-7972-44ea-8708-82e501660dc7 Biomedical Data Science Facility 1259 L'influence du rôle du cycle circadien sur l'immunité 995 563 Pathologie et immunologie 906 565 La Sclérose en plaques 908 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE311046 https://portal.gdc.cancer.gov/projects/TCGA-BLCA https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31684 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE48075 https://www.ebi.ac.uk/biostudies/ArrayExpress/studies/E-MTAB-8494 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112591 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE150050 Nature communications 17 1 caa1e1f3-a370-4a5b-918d-d354fa59c78d Article (Published version) Public s41467-026-69841-y-1.pdf 2839548 application/pdf CC BY-4.0 ad34b16af6ff6825e123ddbbb3b44ec057cfcb03e6d85688bf48373fc32f843b ef0f4f91-75ad-44f3-8594-d9102e40b642 Supplemental data Public 41467_2026_69841_MOESM1_ESM.pdf 5086611 application/pdf ed10ff9e74e020703e1fa2fe1ff1cd1f857914db91088a0368f1b7c6b204b3aa d14534c1-7b4f-49fb-b426-4ca06f83e9c7 Supplemental data Public 41467_2026_69841_MOESM4_ESM(1).xlsx 195596 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 5706d5f1915f49a276963351af0eebc375d3261d62f44760b50fbfb4f6fadd01 openAccess Faculté de médecine / Centre de recherche translationnelle en onco-hématologie Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Centres et instituts / Institut de génétique et de génomique Faculté de médecine / Section de médecine clinique / Département de médecine

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