CCR7 as a novel therapeutic target in t-cell PROLYMPHOCYTIC leukemia

Biomarker Research

Alexandra Schrader¹  Linus Wahnschaffe¹  Marco Herling¹  Sebastian Oberbeck¹  Dennis Jungherz¹  Kostantino Stamatakis²  Manuel Fresno²  Edgar Faber³  Emma I. Andersson⁴  Satu Mustjoki⁵  Javier Loscertales⁶  Fernando Terrón⁷  María Luisa Toribio⁸  Patricia Fuentes⁸  Arantzazu Alfranca⁹  Yaiza Pérez-García⁹  Ana Marcos-Jimenez⁹  Ana Urzainqui⁹  Tamara Mateu-Albero⁹  Anna Kreutzman⁹  Marina Espartero-Santos⁹  Blanca Andrea Sánchez-López⁹  Raquel Juárez-Sánchez^1,10  Carlos Cuesta-Mateos^1,10  Cecilia Muñoz-Calleja^1,11  Lorena Vega-Piris^1,12 

[1] Department I of Internal Medicine, Center for Integrated Oncology (CIO) Aachen-Bonn-Cologne-Duesseldorf (ABCD), Cologne Cluster of Excellence in Cellular Stress Response and Aging-Associated Diseases (CECAD), and Center of Molecular Medicine Cologne (CMMC), The University of Cologne, Cologne, Germany;Department of Cell Biology and Immunology, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain;Department of Hemato-Oncology, Faculty Hospital Olomouc, Faculty of Medicine and Dentistry Palacky University, Olomouc, Czech Republic;Department of Hematology, Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;Department of Hematology, Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;Translational Immunology Research Program and Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland;Hematology Department, Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain;IMMED S.L., Immunological and Medicinal Products, Madrid, Spain;Immune System Development and Function Unit, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain;Immunology Department, Hospital Universitario de La Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain;Immunology Department, Hospital Universitario de La Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain;IMMED S.L., Immunological and Medicinal Products, Madrid, Spain;Immunology Department, Hospital Universitario de La Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain;Universidad Autónoma de Madrid, Madrid, Spain;Methodology Unit, Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain;

关键词: CCR7;    T-PLL;    mAb;    T-cell lymphomas;    Immunotherapy;   

DOI  :  10.1186/s40364-020-00234-z

来源: Springer

【 摘 要 】

T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.

【 授权许可】

CC BY