Soluble type II transforming growth factor-beta receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity.
OBJECTIVE
Transforming growth factor (TGF)-beta 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-beta. The purpose of this study was to explore the possible therapeutic utility of TGF-beta blockade on MM.


METHODS
To evaluate this hypothesis, we tested the effects of a soluble TGF-beta type II receptor (sTGF-beta R) that specifically inhibits TGF-beta1 and TGF-beta 3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-beta) and AB1 (which does not produce TGF-beta).


RESULTS
Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-beta R. In contrast, AB1 tumors showed little response to sTGF-beta 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-beta 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-beta blockade of established TGF-beta-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-beta.
Suzuki
Eiji
E
Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Kapoor
Veena
V
Cheung
H Kam
HK
Ling
Leona E
LE
DeLong
Peter A
PA
Kaiser
Larry R
LR
Albelda
Steven M
SM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005805:Genes, MHC Class I / Q000502:physiology; D005802:Genes, MHC Class II / Q000502:physiology; D008212:Lymphocyte Depletion; D008654:Mesothelioma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D019014:fas Receptor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II