Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms
Jon Celay1, Teresa Lozano2, Axel R Concepcion3,4
1Division of Hematological-Oncology, Center for Applied Medical Research (CIMA), University of Navarra, CIBERONC, IDISNA, Pamplona, Spain.
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.
Insights
Targeting the anion exchanger AE2 with peptide p17AE2 shows promise for cancer therapy. This approach effectively reduces regulatory T cells and induces apoptosis in various cancer cells, offering a new therapeutic strategy for B-cell malignancies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Regulatory T (Treg) cells suppress antitumor immune responses, making their inhibition a potential cancer therapy.
- The Cl-/HCO3- anion exchanger AE2 (SLC4A2) plays a role in intracellular pH regulation and Treg cell numbers.
Purpose of the Study:
- To investigate AE2 as a therapeutic target for cancer by developing peptides that inhibit its function.
- To evaluate the efficacy of AE2-targeting peptides in reducing Treg cells and treating B-cell malignancies.
Main Methods:
- Generation of linear peptides designed to bind the third extracellular loop of AE2.
- Assessment of peptide-induced apoptosis in mouse and human Treg cells and various cancer cell lines.
- Evaluation of a macrocyclic AE2-targeting peptide in a mouse xenograft model of B-cell lymphoma.
Main Results:
- Peptide p17AE2 effectively induced apoptosis in mouse and human Treg cells while activating effector T cells.
- The peptide demonstrated apoptosis-inducing effects on human leukemia, lymphoma, and multiple myeloma cells, with moderate impact on normal B lymphocytes.
- A stable macrocyclic AE2-targeting peptide showed efficacy in mice with B-cell lymphoma xenografts.
Conclusions:
- Targeting the anion exchanger AE2 with specific peptides is a potential therapeutic strategy for B-cell malignancies.
- AE2-targeting peptides can modulate Treg cell function and directly induce apoptosis in malignant B cells.
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