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Cell Therapy & Immunotherapy
Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms
Jon Celay,1* Teresa Lozano,2* Axel R. Concepcion,3,4 Elena Beltrán,1,5 Francesc Rudilla,2 María José García-Barchino,1 Eloy F. Robles,1 Obdulia Rabal,6 Irene de Miguel,6 Carlos Panizo,7 Noelia Casares,2 Julen Oyarzabal,6 Jesús Prieto,2,3 Juan F. Medina,3 Juan José Lasarte2** and José Ángel Martínez-Climent1**
1Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain; 2Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; 3Division of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; 4Department of Pathology, New York University School of Medicine, New York, NY, USA; 5Department of Pharmacology, University of Navarra, Pamplona, Spain; 6Small Molecule Discovery Platform and Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain and 7Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain
ABSTRACT
Ferrata Storti Foundation
*These authors contributed equally to the study and should both be considered first authors. **These authors contributed equally to the study and should both be considered senior and corresponding authors
Haematologica 2018 Volume 103(6):1065-1072
Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising thera- peutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl–/HCO – anion exchanger AE2 (also termed
3
SLC4A2), a membrane-bound carrier involved in intracellular pH regula-
tion, 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.
Introduction
Despite the use of new diagnostic and therapeutic strategies that have improved the prognosis of mature B-cell malignancies, most patients cannot be cured with cur- rently available therapies.1,2 To improve the clinical outcome of these patients, novel agents against specific cellular targets are being developed and tested.3,4 In addition, different types of therapy have become standard treatments for certain hematologic malignancies, while others undergo clinical testing.5,6 Among these, a promising experimental approach aims to inhibit the CD4+CD25+Foxp3+ T regulatory (Treg) cells, and prevent their suppressor activity against antitumoral T helper and cytotoxic T cells.7,8 The use of therapies combining a direct antitumoral effect with an enhance- ment of the T cell-mediated immune responses would represent a major advance in the treatment of B-cell malignancies.9
The regulation of intracellular pH (pHi) is critical for important cellular processes and functions in many cell types, including lymphocytes.10–12 To achieve acid–base
Correspondence:
jamcliment@unav.es or jlasarte@unav.es
Received: July 10, 2017.
Accepted: November 24, 2017. Pre-published: November 30, 2017.
doi:10.3324/haematol.2017.175687
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/1065
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haematologica | 2018; 103(6)
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