TY - JOUR
T1 - Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment
AU - Roehlen, Natascha
AU - Muller, Marion
AU - Nehme, Zeina
AU - Crouchet, Emilie
AU - Jühling, Frank
AU - Del Zompo, Fabio
AU - Cherradi, Sara
AU - Duong, Francois H.T.
AU - Almeida, Nuno
AU - Saviano, Antonio
AU - Fernández-Vaquero, Mirian
AU - Riedl, Tobias
AU - El Saghire, Houssein
AU - Durand, Sarah C.
AU - Ponsolles, Clara
AU - Oudot, Marine A.
AU - Martin, Romain
AU - Brignon, Nicolas
AU - Felli, Emanuele
AU - Pessaux, Patrick
AU - Lallement, Antonin
AU - Davidson, Irwin
AU - Bandiera, Simonetta
AU - Thumann, Christine
AU - Marchand, Patrice
AU - Moll, Solange
AU - Nicolay, Brandon
AU - Bardeesy, Nabeel
AU - Hoshida, Yujin
AU - Heikenwälder, Mathias
AU - Iacone, Roberto
AU - Toso, Alberto
AU - Meyer, Markus
AU - Elson, Greg
AU - Schweighoffer, Tamas
AU - Teixeira, Geoffrey
AU - Zeisel, Mirjam B.
AU - Laquerriere, Patrice
AU - Lupberger, Joachim
AU - Schuster, Catherine
AU - Mailly, Laurent
AU - Baumert, Thomas F.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - CLDN1
KW - HCC
KW - Liver cancer
KW - plasticity
KW - resistance
KW - stemness
KW - tight junction
KW - tumor immune microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85144363002&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144363002&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2022.10.011
DO - 10.1016/j.jhep.2022.10.011
M3 - Article
C2 - 36309131
AN - SCOPUS:85144363002
SN - 0168-8278
VL - 78
SP - 343
EP - 355
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -