Nectin-4 reduces T cell effector function and is a therapeutic target in pancreatic cancer

Max Heiduk; Carolin Beer; Sarah Cronjaeger; Emily A. Kawaler; Ulrich Sommer; Franziska Baenke; David Digomann; Loreen Natusch Bufe; Charlotte Reiche; Jessica Glück; Franziska Hoffmann; Sungsik Kim; Daniel E. Stange; Diane M. Simeone; Jürgen Weitz; Lena Seifert; Adrian M. Seifert

doi:10.1172/jci.insight.194290

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Heiduk, M. in: PubMed | Google Scholar |

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Glück, J. in: PubMed | Google Scholar

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

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¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Kim, S. in: PubMed | Google Scholar

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Stange, D. in: PubMed | Google Scholar

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Simeone, D. in: PubMed | Google Scholar

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Weitz, J. in: PubMed | Google Scholar |

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Seifert, L. in: PubMed | Google Scholar |

¹Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

²Perlmutter Cancer Center, NYU Langone Health, New York, United States of America

³Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

⁴Department of Surgery, Moores Cancer Center, UC San Diego Health, San Diego, United States of America

Find articles by Seifert, A. in: PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.194290.
Copyright © 2025, Heiduk et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published December 9, 2025 - Version history

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, immunohistochemistry from primary tumors, and single-cell RNA sequencing 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. Further, 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 and regulatory T cells 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 underscores Nectin-4 as a novel therapeutic target and provides the rationale to test this agent in PDAC patients.

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Nectin-4 reduces T cell effector function and is a therapeutic target in pancreatic cancer

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