title: Novel TGF-beta antagonist inhibits tumor growth and angiogenesis by inducing IL-2 receptor-driven STAT1 activation.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penafuerte
authors.forename: Norma
authors.initials: N
authors.lastname: Bautista-Lopez
authors.forename: Manaf
authors.initials: M
authors.lastname: Bouchentouf
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Kathy
authors.initials: K
authors.lastname: Forner
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D053646:Interleukin-2 Receptor beta Subunit; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D053646:Interleukin-2 Receptor beta Subunit; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016212:Transforming Growth Factor beta