An Anti–Transforming Growth Factor β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments

Abstract

Overexpression of transforming growth factor B (TGF-B) is frequently associated with metastasis and poor prognosis, and TGF-B antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti-TGF-B antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1;) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-B expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-B antibodies reverse this effect, and the absence of a major effect of TGF-B antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications. [Cancer Res 2008;68(10):3835-43]

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

“…In our study, we used two strategies to block TGF-β signaling: (i) in a genetic model, TGF-β signaling was inhibited by stable transfection of tumor cells with a soluble TGF-β receptor (sTβRII), which functions as a "TGF-β trap," competing with TGF-β1 and -β3 for binding to TGF-β receptor ΙΙ; and (ii) in a pharmacologic model, TGF-β signaling was inhibited by a neutralizing antibody that blocks all three isoforms of TGF-β. The 4T1 tumors are known to express elevated levels of TGF-β and are sensitive to TGF-β blockade (4,8). We observed that both sTβRII transfection and 1D11 antibody administration significantly inhibited 4T1 tumor growth and metastasis.…”

“…), impaired intratumoral drug delivery is an important physiological factor contributing toward chemoresistance (1,2). TGF-β is an important regulator of normal mammary gland development and function, as well as of the progression of mammary carcinomas (3)(4)(5)(6)(7)(8). Although the role of TGF-β in tumor progression and metastasis has been studied extensively, little is known about its impact on drug delivery.…”

Roles of TGFβ in metastasis

“…Additionally, other groups have shown that the spread of a transplantable model of metastatic breast cancer, 4T1 breast cancer cells, can be efficiently suppressed by administering an antibody that targets all three isoforms of the TGFb ligand. This work went on to show that TGFb neutralizing antibodies can have multiple cooperative effects on angiogenesis, immune cell function, and tumor cell viability, eventually leading to effective tumor control and reductions in metastasis [92]. These results illustrate the capacity to target the TGFb pathway in order to effectively inhibit metastatic events.…”

An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

“…TGF-␤'s disease promoting activities, together with animal studies that have demonstrated beneficial effects of inhibiting TGF-␤ in models of cancer and fibrosis (15)(16)(17)(18)(19)(20)(21)(22), have made them important targets for the development of inhibitors. However, despite clinical trials ongoing for nearly 2 decades using receptor kinase inhibitors, neutralizing antibodies, and other approaches, no TGF-␤ inhibitors have been approved for clinical use in humans (23,24).…”