Journal Article

DKFZ-2026-00201

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Nectin-4 reduces T cell effector function and is a therapeutic target in pancreatic cancer.

Heiduk, M. ; Beer, C. ; Cronjaeger, S. ; Kawaler, E. A. ; Sommer, U. ; Baenke, F.DKFZ* ; Digomann, D.DKFZ* ; Bufe, L. N.DKFZ* ; Reiche, C. ; Glück, J. ; Hoffmann, F. ; Kim, S. ; Stange, D. E.DKFZ* ; Simeone, D. M. ; Weitz, J.DKFZ* ; Seifert, L.DKFZ* ; Seifert, A. M.DKFZ*

2026
JCI Insight Ann Arbor, Michigan

Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and current therapies show limited efficacy. Ligands and receptors of the TIGIT axis were analyzed using multicolor flow cytometry of tumor and blood samples, IHC from primary tumors, and single-cell RNA-Seq from primary tumors and liver metastasis from patients with various stages of PDAC. The effect of soluble and plate-bound Nectin-4 on T cell function was tested in vitro. Furthermore, patient-derived PDAC organoids were treated with the standard-of-care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin. TIGIT expression was increased on tumor-infiltrating conventional T cells and Tregs compared with T cells from matched blood. Nectin-4 but not CD155 expression was associated with poor outcome. Nectin-4 was exclusively expressed by tumor cells and correlated with low immune infiltration. Notably, Nectin-4 inhibited T cell effector cytokine production in vitro. Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscore Nectin-4 as a potential novel therapeutic target and provide the rationale to test this agent in patients with PDAC.

Keyword(s): Humans (MeSH) ; Pancreatic Neoplasms: drug therapy (MeSH) ; Pancreatic Neoplasms: immunology (MeSH) ; Pancreatic Neoplasms: pathology (MeSH) ; Pancreatic Neoplasms: metabolism (MeSH) ; Carcinoma, Pancreatic Ductal: drug therapy (MeSH) ; Carcinoma, Pancreatic Ductal: immunology (MeSH) ; Carcinoma, Pancreatic Ductal: pathology (MeSH) ; Cell Adhesion Molecules: metabolism (MeSH) ; Cell Adhesion Molecules: immunology (MeSH) ; Cell Adhesion Molecules: genetics (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: drug effects (MeSH) ; Receptors, Immunologic: metabolism (MeSH) ; Deoxycytidine: analogs & derivatives (MeSH) ; Gemcitabine (MeSH) ; Female (MeSH) ; Antineoplastic Combined Chemotherapy Protocols: therapeutic use (MeSH) ; Antineoplastic Combined Chemotherapy Protocols: pharmacology (MeSH) ; Animals (MeSH) ; Cell Line, Tumor (MeSH) ; Paclitaxel (MeSH) ; Lymphocytes, Tumor-Infiltrating: immunology (MeSH) ; Mice (MeSH) ; Leucovorin (MeSH) ; Male (MeSH) ; Oxaliplatin (MeSH) ; Nectins (MeSH) ; Cancer ; Gastroenterology ; Oncology ; T cells ; NECTIN4 protein, human ; Cell Adhesion Molecules ; TIGIT protein, human ; Receptors, Immunologic ; Deoxycytidine ; Gemcitabine ; Paclitaxel ; Leucovorin ; Oxaliplatin ; Nectins

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Dresden (DD01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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