title: Expression of interleukin-4 receptor alpha in human pleural mesothelioma is associated with poor survival and promotion of tumor inflammation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pathology, The Brigham & Women's Hospital, Boston, MA, USA. bburt@partners.org
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Burt
authors.forename: Andrew
authors.initials: A
authors.lastname: Bader
authors.forename: Daniel
authors.initials: D
authors.lastname: Winter
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit / Q000097:blood / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D010997:Pleural Neoplasms / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis
chemical_list: D053662:Interleukin-4 Receptor alpha Subunit; D015847:Interleukin-4