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

Abstract

Purpose: Transforming growth factor (TGF)-␤ 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-␤. The purpose of this study was to explore the possible therapeutic utility of TGF-␤ blockade on MM.Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF-␤ type II receptor (sTGF-␤R) that specifically inhibits TGF-␤1 and TGF-␤3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-␤) and AB1 (which does not produce TGF-␤).Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-␤R. In contrast, AB1 tumors showed little response to sTGF-␤R. 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-␤R 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-␤ blockade of established TGF-␤-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-␤.

Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17

“…We further showed that IL-17 could directly promote survival of 4T1 tumor cells, both in vitro and in vivo, thus providing a plausible explanation for the tumor-promoting effect of CD8+ T cells in this model. Many tumors are already known to evade immune surveillance by compromising the development or activity of tumor-specific cytotoxic T-cells, often in a TGF-h-dependent manner (3,15,16,19,37,42,43). However, our data suggest that some tumors may go further, creating a local cytokine environment that actively skews local differentiation or expansion of CD8+ T cells to a state where they directly promote tumor growth.…”

“…In addition, immunoregulatory cells, such as T regs and NKT cells may either make or induce production of TGF-h (14,15). Furthermore, there is a growing body of data suggesting that strategies to antagonize TGF-h can suppress tumorigenesis by enhancing or restoring effective antitumor immune surveillance (15)(16)(17)(18)(19)(20)(21), thus underscoring the potential relevance of this mechanism to carcinogenic progression.…”

The Role of Immunotherapy in the Treatment of Mesothelioma

“…CD8 + T cells were responsible for tumour cell killing following treatment, but were less efficient in bulky TGF- secreting tumours. Furthermore, complete regressions were not observed (Suzuki et al, 2004).…”

The Role of Inflammation in Development and Therapy of Malignant Mesothelioma

“…TGF-β has received attention as a therapeutic target based on in vivo studies that demonstrated blocking of TGF-β by neutralizing antibodies, TGF inhibitors and other methods resulted in MM tumor inhibition (Marzo et al, 1997;Suzuki et al, 2004;. A phase II clinical trial investigating the use of an anti-TGF monoclonal antibody, GC1008, in relapsed MPM patients is in progress.…”