Aptamer-mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

Cancer Res. 2012 Mar 15;72(6):1373-83. doi: 10.1158/0008-5472.CAN-11-2772. Epub 2012 Jan 26.

Abstract

In addition to promoting tumor progression and metastasis by enhancing angiogenesis and invasion, myeloid-derived suppressor cells (MDSC) and tumor-associated macrophage (TAM) also inhibit antitumor T-cell functions and limit the efficacy of immunotherapeutic interventions. Despite the importance of these leukocyte populations, a simple method for their specific depletion has not been developed. In this study, we generated an RNA aptamer that blocks the murine or human IL-4 receptor-α (IL4Rα or CD124) that is critical for MDSC suppression function. In tumor-bearing mice, this anti-IL4Rα aptamer preferentially targeted MDSCs and TAM and unexpectedly promoted their elimination, an effect that was associated with an increased number of tumor-infiltrating T cells and a reduction in tumor growth. Mechanistic investigations of aptamer-triggered apoptosis in MDSCs confirmed the importance of IL4Ra-STAT6 pathway activation in MDSC survival. Our findings define a straightforward strategy to deplete MDSCs and TAMs in vivo, and they strengthen the concept that IL4Rα signaling is pivotal for MDSC survival. More broadly, these findings suggest therapeutic strategies based on IL4Rα signaling blockades to arrest an important cellular mechanism of tumoral immune escape mediated by MDSCs and TAM in cancer.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Aptamers, Nucleotide / pharmacology*
  • Carcinoma / drug therapy*
  • Carcinoma / immunology
  • Cell Line, Tumor
  • Disease Progression*
  • Humans
  • Interleukin-4 Receptor alpha Subunit / antagonists & inhibitors
  • Interleukin-4 Receptor alpha Subunit / immunology
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / immunology
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / immunology
  • STAT6 Transcription Factor / metabolism
  • Tumor Escape / drug effects
  • Tumor Escape / immunology

Substances

  • Aptamers, Nucleotide
  • IL4R protein, human
  • Il4ra protein, mouse
  • Interleukin-4 Receptor alpha Subunit
  • Receptors, Cell Surface
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stat6 protein, mouse