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Soluble Type II Transforming Growth Factor-ß Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity

¹ Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania; and ² Molecular and Cellular Biology, Biogen Idec, Cambridge, Massachusetts

Purpose: Transforming growth factor (TGF)-ß blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-ß. The purpose of this study was to explore the possible therapeutic utility of TGF-ß blockade on MM.

Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF-ß type II receptor (sTGF-ßR) that specifically inhibits TGF-ß1 and TGF-ß3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-ß) and AB1 (which does not produce TGF-ß).

Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-ßR. In contrast, AB1 tumors showed little response to sTGF-ßR. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8⁺ T cells and (b) CD8⁺ T cells isolated from spleens of mice treated with sTGF-ßR showed strong antitumor cytolytic effects, whereas CD8⁺ T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects.

Conclusions: Our data suggest that TGF-ß blockade of established TGF-ß-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-ß.

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