Immune Signature of Malignant Pleural Mesothelioma as Assessed by Transcriptome Analysis

Malignant pleural mesothelioma (MPM) is a highly malignant tumor arising in patients previously exposed to asbestos fibers. Its increasing incidence and its social, financial and human impact have become a frequent problem in many industrialized countries. The unresponsiveness of malignant mesothelioma to conventional therapies has led clinicians to develop new treatments. As immunotherapy has been shown to offer promising and targeted treatment of MPM patients, the knowledge of the immunoresistance level of MPM may be a valuable tool for "à la carte" therapy. In a previous work, we profiled the gene expression of two MPM tissues compared to healthy mesothelial cells using a 10K cDNA microarray. Subsequent clustering analysis identified several clusters of differentially-expressed genes among those that are functionally-related to the immune system. In this report, we focus on genes with expression changes that may facilitate tumor escape from immune-mediated rejection. We also analyzed the immune reaction by staining the immunocompetent cells surrounding the tumor. Interestingly, the tumor with the strongest escape response, as shown by the expression of numerous immunoresistance-associated genes, displayed the strongest T cell infiltrate. The main genes conferring immunoresistance are CD74, HLADOA, HLADMB, PTGS1, IGFBP7 and TGFB3, by favoring immune tolerance, and CFLAR, DFFA, TNFRSF6, BNIP3L by impairing apoptosis. These observations have fundamental consequences in the understanding of immunological properties of MPM, and offer a new insight into the mechanisms whereby MPM may circumvent host-mediated immune activities and promotes its own development. For an immunomodulation strategy to cure mesothelioma, it is crucial to characterize the MPM "immune signature" to design adapted immunotherapies.