Mechanisms of immune suppression exerted by regulatory T-cells in subcutaneous AE17 murine mesothelioma.

We have reported previously that a combined intratumoral treatment with anti-CD25mAb/transforming growth factor-β (TGF-β) soluble receptor induced regression of established and subcutaneous AE17 murine mesotheliomas. Here, we have investigated the mechanisms underlying this observation by analyzing the concentrations of interferon-γ (IFN-γ) and TGF-β within tumors at various time points following single regulatory T-cell (T(reg)) depleting anti-CD25mAb, TGF-β soluble receptor, or combined anti-CD25mAb/TGF-β soluble receptor treatment. The combined treatment maintains the intratumoral TGF-β concentration at a significantly lower level than either the untreated controls or the single anti-CD25mAb treatment alone. Also, the lower level of TGF-β correlated with a significantly higher concentration of IFN-γ compared with the single anti-CD25mAb treatment. It was hypothesized that TGF-β was the master regulator of immune suppression in the AE17 model of mesothelioma. However, it was found that although important, this cytokine alone is not responsible for maintaining immune suppression and that multiple mechanisms of suppression exist. Specifically, we have shown that the presence of T(regs) in the tumor draining lymph nodes alters the phenotype of dendritic cells in the same location. These data suggest that because the antitumor immune response is inhibited by multiple mechanisms of suppression, development of immunotherapeutic treatment regimes will be more successful if these mechanisms can be simultaneously inhibited.