Abstract
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. 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. 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. 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.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive tumor that arises from the mesothelial lining of the pleura
To confirm the expression of interleukin-4 receptor a (IL-4Ra) on tumor cells from human MPM tumor specimens, we carried out flow cytometry on the CD45-negative cell fraction of tumor mononuclear cell suspensions, where high frequencies of IL-4Ra– positive cells were found (Fig. 2A)
A small, scattered fraction of cells in the stromal compartment of the tumor stained positive for IL-4Ra, the great majority of IL4Ra staining was found on the tumor cells themselves
Summary
Malignant pleural mesothelioma (MPM) is an aggressive tumor that arises from the mesothelial lining of the pleura. It is a unique malignancy whose primary mode of spread is invasion of surrounding tissues and whose proclivity for distant metastases is low. MPM is a highly fatal tumor that is resilient to single modality treatment with surgery, chemotherapy, or radiation. With multimodality therapy in selected patients, median survival is 19 months [1]. Two-thirds of patients with MPM have epithelial histology. The remaining one third of patients have nonepithelial histology (sarcomatoid or biphasic), which are Authors' Affiliations: 1Division of Thoracic Surgery, and 2Department of Pathology, The Brigham & Women's Hospital, Boston, Massachusetts
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