Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Expression of IL-4Rα by human MPM tumors was determined by quantitative real-time PCR (<i>n</i> = 37) and immunohistochemistry (<i>n</i> = 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.</p><p><b>Results:</b> 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; <i>P</i> = <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 (<i>P</i> = 0.04). A greater percentage of tumor-infiltrating T cells produced IL-4 compared with matched blood T cells (21% ± 7% vs. 4% ± 2%, <i>P</i> = 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.</p><p><b>Conclusions:</b> 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 <i>in situ</i>. The IL-4/IL-4 receptor axis is a potential therapeutic target in human MPM. <i>Clin Cancer Res; 18(6); 1568–77. ©2012 AACR</i>.</p></div>

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