Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms.

Abstract

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.

• Authors: 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
• Journal: Haematologica (Haematologica) Vol. 103 Issue 6 Pg. 1065-1072 (06 2018) ISSN: 1592-8721 [Electronic] Italy
• PMID: 29191842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Ferrata Storti Foundation.

Chemical References

• Anions
• Antineoplastic Agents
• Chloride-Bicarbonate Antiporters
• Peptides

Topics

• Animals
• Anions (metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chloride-Bicarbonate Antiporters (antagonists & inhibitors)
• Disease Models, Animal
• Humans
• Leukemia, B-Cell (drug therapy, metabolism, pathology)
• Lymphoma, B-Cell (drug therapy, metabolism, pathology)
• Mice
• Mice, Knockout
• Peptides (pharmacology)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Xenograft Model Antitumor Assays