Details

Autor(en) / Beteiligte

• Penafuerte, Claudia
• Bautista-Lopez, Norma
• Bouchentouf, Manaf
• Birman, Elena
• Forner, Kathy
• Galipeau, Jacques

Titel

Novel TGF-beta antagonist inhibits tumor growth and angiogenesis by inducing IL-2 receptor-driven STAT1 activation

Ist Teil von

• The Journal of immunology (1950), 2011-06, Vol.186 (12), p.6933-6944

Ort / Verlag

United States

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• Carcinoma derived TGF-β acts as a potent pro-oncogenic factor and suppresses antitumor immunity. To antagonize TGF-β-mediated effects in tandem with a proinflammatory immune stimulus, we generated a chimeric protein borne of the fusion of IL-2 and the soluble extracellular domain of TGF-βR II (FIST). FIST acts as a decoy receptor trapping active TGF-β in solution and interacts with IL-2-responsive lymphoid cells, inducing a distinctive hyperactivation of STAT1 downstream of IL-2R, which in turn promotes SMAD7 overexpression. Consequently, FIST-stimulated lymphoid cells are resistant to TGF-β-mediated suppression and produce significant amounts of proinflammatory cytokines. STAT1 hyperactivation further induces significant secretion of angiostatic CXCL10. Moreover, FIST upregulates T-bet expression in NK cells promoting a potent Th1-mediated antitumor response. As a result, FIST stimulation completely inhibits pancreatic cancer (PANC02) and melanoma (B16) tumor growth in immunocompetent C57BL/6 mice. In addition, melanoma cells expressing FIST fail to form tumors in CD8(-/-), CD4(-/-), B cell-deficient (μMT), and beige mice, but not in NOD-SCID and Rag2/γc knockout mice, consistent with the pivotal role of FIST-responsive, cancer-killing NK cells in vivo. In summary, FIST constitutes a novel strategy of treating cancer that targets both the host's angiogenic and innate immune response to malignant cells.