Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment

Article Article scientifique Article Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment eng 2022-10-27 2023-02 author Roehlen Natascha author Muller Marion author Nehme Zeina author Crouchet Emilie author Jühling Frank author Del Zompo Fabio author Cherradi Sara author Duong Francois H T author Almeida Nuno Francisco 628373 author Saviano Antonio author Fernández-Vaquero Mirian author Riedl Tobias author El Saghire Houssein author Durand Sarah C author Ponsolles Clara author Oudot Marine A author Martinuzzi Romain Benoît 853985 author Brignon Nicolas author Felli Emanuele author Pessaux Patrick author Lallement Antonin author Davidson Irwin author Bandiera Simonetta author Thumann Christine author Marchand Patrice author Moll Solange 28349 author Nicolay Brandon author Bardeesy Nabeel author Hoshida Yujin author Heikenwälder Mathias author Iacone Roberto author Toso Alberto author Meyer Markus 535658 author Elson Greg author Schweighoffer Tamas author Teixeira Geoffrey author Zeisel Mirjam B author Laquerriere Patrice author Lupberger Joachim author Schuster Catherine author Mailly Laurent author Baumert Thomas F 343-355 10.1016/j.jhep.2022.10.011 36309131 0168-8278 Background & aims: Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. Methods: Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. Results: Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. Conclusions: Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. Impact and implications: Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology. CLDN1 HCC Liver cancer Plasticity Resistance Stemness Tight junction Tumor immune microenvironment Humans Animals Mice Carcinoma, Hepatocellular / genetics Claudin-1 / genetics Liver Neoplasms / genetics Carcinogens Tumor Microenvironment Antibodies, Monoclonal / pharmacology Antibodies, Monoclonal / therapeutic use Cell Line, Tumor Dewey 616.07 137 Département de pathologie et immunologie 21F false 393 Analyse protéomique et Analyse génomique des maladies rénales 659 Journal of hepatology 78 2 d47fd157-04db-483c-9942-045b30bea4e9 Article (Published version) Public Article-scientifique-from-unpaywall.pdf 4957112 application/pdf CC BY-NC-ND-4.0 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment	Journal of hepatology			2023	316	344

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Martinuzzi, Romain Benoît