Microenvironment and Immunology of the Human Pleural Malignant Mesothelioma

Abstract

Human malignant pleural mesothelioma (MPM) is strongly related to pre-existing and long-lasting conditions of chronic inflammation and tissue injury, caused by the inhalation of airborne asbestos fibers. The local immunological network and especially inflammatory cells of the innate immunity play a major role in tumor onset and development, by fueling and perpetuating this state of non-resolving inflammation. Reactive oxygen and nitrogen species and inflammatory cytokines increase the risk of DNA damage and mutations in specific genes; the proliferative pressure posed by available growth factors, combined with an immunosuppressive microenvironment, leads to full-blown carcinogenesis of pleural cells. In established MPM tissues, abundant leukocyte infiltration represents the inflammatory signature of this tumor, and its presence is either associated with poor prognosis (predominance of macrophages and Tregs) or, in some cases, with longer survival (predominance of T cells as evidence of antitumor responses). Fibroblasts and deregulated neo-angiogenesis also participate to create an aberrant tumoral stroma where several cytokines, growth factors, and proteolytic enzymes are present and ultimately lead to sustain cancer cell survival, proliferation, and spreading. Tumor-induced immune tolerance and its intrinsic resistance to therapies render malignant mesothelioma a particularly difficult challenge in oncology.