Purpose: Transforming growth factor (TGF)-β 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-β. The purpose of this study was to explore the possible therapeutic utility of TGF-β blockade on MM.

Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF-β type II receptor (sTGF-βR) that specifically inhibits TGF-β1 and TGF-β3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-β) and AB1 (which does not produce TGF-β).

Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-βR. In contrast, AB1 tumors showed little response to sTGF-βR. 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-βR 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-β blockade of established TGF-β-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-β.