Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides

Tammy Price-Troska, Zhi Zhang Yang, David Diller, Alexander Bayden, Mark Jarosinski, Joseph Audie, Stephen Maxted Ansell

Research output: Contribution to journalArticle

Abstract

Summary: Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (Treg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8+ T cells co-cultured with IL-2–stimulated CD4+ T cells that had been pretreated with CMD178 compared to CD8+ cells co-cultured with untreated IL-2–stimulated CD4+ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit Treg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Apr 26 2018

    Fingerprint

Keywords

  • Computationally designed peptides
  • Foxp3
  • Soluble IL-2Ra
  • STAT5
  • T cells

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this