Expression of interleukin-4 receptor alpha in human pleural mesothelioma is associated with poor survival and promotion of tumor inflammation

Clin Cancer Res. 2012 Mar 15;18(6):1568-77. doi: 10.1158/1078-0432.CCR-11-1808. Epub 2012 Jan 18.


Purpose: The origin and pathogenesis of malignant pleural mesothelioma (MPM) are closely aligned with inflammation. MPM tumors express interleukin-4 receptor α (IL-4Rα), the principal subunit of the IL-4 receptor. We set out to determine the biologic function and clinical relevance of IL-4Rα in human MPM.

Experimental design: Expression of IL-4Rα by human MPM tumors was determined by quantitative real-time PCR (n = 37) and immunohistochemistry (n = 52). Intracellular cytokine analysis of T-cell-derived IL-4 was carried out on matched tumor and blood samples from eight patients with MPM. Four human MPM cell lines were used to determine the direct effects of IL-4 on MPM tumor cells.

Results: High tumor mRNA expression of IL-4Rα was an independent predictor of poor survival in patients with epithelial MPM [HR, 3.13, 95% confidence interval (CI), 1.68-7.15; P = <0.0001]. Ninety-seven percent of epithelial MPM tumors and 95% of nonepithelial MPM tumors expressed IL-4Rα protein by immunohistochemistry, and strong IL-4Rα staining correlated with worse survival in patients with epithelial histology (P = 0.04). A greater percentage of tumor-infiltrating T cells produced IL-4 compared with matched blood T cells (21% ± 7% vs. 4% ± 2%, P = 0.0002). In response to IL-4, human MPM cells showed increased STAT-6 phosphorylation and increased production of IL-6, IL-8, and VEGF, without effect on proliferation or apoptosis.

Conclusions: Tumor expression of IL-4Rα is inversely correlated with survival in patients undergoing surgical resection for epithelial MPM. Tumor-infiltrating T cells in MPMs are polarized to produce IL-4 and may provide endogenous activation signals to MPM tumor cells in situ. The IL-4/IL-4 receptor axis is a potential therapeutic target in human MPM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Female
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism
  • Interleukin-4 / metabolism
  • Interleukin-4 Receptor alpha Subunit / blood
  • Interleukin-4 Receptor alpha Subunit / metabolism*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Mesothelioma / blood
  • Mesothelioma / immunology
  • Mesothelioma / metabolism*
  • Mesothelioma / mortality
  • Pleural Neoplasms / blood
  • Pleural Neoplasms / immunology
  • Pleural Neoplasms / metabolism*
  • Pleural Neoplasms / mortality
  • Prognosis


  • Interleukin-4 Receptor alpha Subunit
  • Interleukin-4