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

Autor:	Roehlen N; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Muller M; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; CNRS, Institut Pluridisciplinaire Hubert Curien UMR 7178, Strasbourg, France., Nehme Z; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Crouchet E; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Jühling F; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Del Zompo F; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Cherradi S; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Duong FHT; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Almeida N; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Saviano A; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France., Fernández-Vaquero M; Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany., Riedl T; Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany., El Saghire H; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Alentis Therapeutics, Basel, Switzerland., Durand SC; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Ponsolles C; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Oudot MA; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Martin R; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Brignon N; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Felli E; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France., Pessaux P; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France., Lallement A; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UDS, Illkirch, France., Davidson I; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UDS, Illkirch, France., Bandiera S; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Thumann C; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Marchand P; Université de Strasbourg, Strasbourg, France; CNRS, Institut Pluridisciplinaire Hubert Curien UMR 7178, Strasbourg, France., Moll S; Department of Pathology, University Hospital of Geneva, Switzerland., Nicolay B; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA., Bardeesy N; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA., Hoshida Y; Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA., Heikenwälder M; Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany., Iacone R; Alentis Therapeutics, Basel, Switzerland., Toso A; Alentis Therapeutics, Basel, Switzerland., Meyer M; Alentis Therapeutics, Basel, Switzerland., Elson G; Alentis Therapeutics, Basel, Switzerland., Schweighoffer T; Alentis Therapeutics, Basel, Switzerland., Teixeira G; Alentis Therapeutics, Basel, Switzerland., Zeisel MB; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), Lyon, France., Laquerriere P; Université de Strasbourg, Strasbourg, France; CNRS, Institut Pluridisciplinaire Hubert Curien UMR 7178, Strasbourg, France., Lupberger J; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Schuster C; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Mailly L; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France., Baumert TF; Université de Strasbourg, Strasbourg, France; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France; Institut Universitaire de France (IUF), Paris, France. Electronic address: thomas.baumert@unistra.fr.
Jazyk:	angličtina
Zdroj:	Journal of hepatology [J Hepatol] 2023 Feb; Vol. 78 (2), pp. 343-355. Date of Electronic Publication: 2022 Oct 27.
DOI:	10.1016/j.jhep.2022.10.011
Abstrakt:	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. (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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