Mesothelioma environment comprises cytokines and Treg cells that suppress immune responses

European Respiratory Journal. 2006 Mar 15; [Epub ahead of print] [Link]

J.P.J.J. Hegmans 1*, A. Hemmes 1, H. Hammad 1, L. Boon 2, H.C. Hoogsteden 1, B.N. Lambrecht 1

1 Dept of Pulmonary Medicine, Erasmus MC, Rotterdam
2 Bioceros B.V., Utrecht, The Netherlands


Malignant mesothelioma is a cancer with dismal prognosis. Our objective was to address the role of the immune system, tumour microenvironment and potential immunosuppression in mesothelioma.

Expression profiles of 80 cytokines were determined in the supernatant of mesothelioma cell lines and the original patient’s pleural effusion. Influx of immune effector cells was detected by immunohistochemistry.

Angiogenin, VEGF, TGF{beta}, ENA-78 and several other proteins involved in immune suppression, angiogenesis and plasma extravasation could be detected in both supernatant and pleural effusion. Surrounding stroma and/or infiltrating cells were the most likely source of HGF, MIP-1{delta}, MIP-3{alpha}, NAP-2, and PARC that can cause leukocyte infiltration and activation. There was a massive influx of CD4+ and CD8+ T lymphocytes and macrophages, but not of dendritic cells, in human mesothelioma biopsies. We further demonstrated that human mesothelioma tissue contained significant amounts of Foxp3+CD4+CD25+ regulatory T cells. When these CD25+ regulatory T cells were depleted in an in vivo mouse model, survival was increased.

Mesothelioma is infiltrated by immune effector cells, but also contains cytokines and regulatory T cells that suppress an efficient immune response. Immunotherapy of mesothelioma might be more effective when combined with drugs that eliminate or control regulatory T cells.