Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms
Jon Celay,
Teresa Lozano,
Axel R. Concepcion,
Elena Beltrán,
Francesc Rudilla,
María José García-Barchino,
Eloy F. Robles,
Obdulia Rabal,
Irene de Miguel,
Carlos Panizo,
Noelia Casares,
Julen Oyarzabal,
Jesús Prieto,
Juan F. Medina,
Juan José Lasarte,
José Ángel Martínez-Climent
Affiliations
Jon Celay
Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain
Teresa Lozano
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Axel R. Concepcion
Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;Department of Pathology, New York University School of Medicine, New York, NY, USA
Elena Beltrán
Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain;Department of Pharmacology, University of Navarra, Pamplona, Spain
Francesc Rudilla
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
María José García-Barchino
Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain
Eloy F. Robles
Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain
Obdulia Rabal
Small Molecule Discovery Platform and Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Irene de Miguel
Small Molecule Discovery Platform and Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Carlos Panizo
Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain
Noelia Casares
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Julen Oyarzabal
Small Molecule Discovery Platform and Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Jesús Prieto
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain;Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Juan F. Medina
Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Juan José Lasarte
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
José Ángel Martínez-Climent
Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain
Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl−/HCO3− anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.