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.

The therapeutic importance of acid-base balance

“…The acidic tumor microenvironment promotes an anti-inflammatory T-cell response (see section 5.6.1), but the deletion of AE2 promotes a pro-inflammatory T-cell response (see section 4.12.1). Therefore inhibition of T-cell AE2 could be a valuable paradigm for enhancing a cytotoxic immune response [435] .…”

Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration

“…Accumulating evidence suggests that AE2 is involved in tumorigenesis. Celay et al addressed the role of AE2 and its target peptide reduced tumor growth in vivo [30]. Enhanced AE2 promotes ovarian cancer progression by activating mTOR signaling [17]; whereas, reduction of AE2 enhances cellular migration via the activation of MMP pathways in the esophageal squamous cell carcinoma [31].…”

Primary biliary cholangitis: pathogenic mechanisms

“…As mentioned, in PBC, AE2 mRNA levels are decreased not only in the liver but also in peripheral lymphoid cells [ 43 ▪▪ ]. Thus, altered pHi because of defective AE2 activity may affect the function of immune cells in PBC patients [ 48 , 89 ]. Indeed, we found that Ae2a,b -deficient mice exhibit reduced Treg population, progressive expansion of CD8 + T cells and increased production of IL-12 and IFNγ [ 46 , 47 ].…”