title: Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice.
abstract: TNF is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)-injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2-Fc fusion protein (TNFR2-Fc) treatment or TNF gene deletion. In addition, gene deletion of TNFR1, which is preferentially triggered by sTNF, was temporarily blocked, whereas gene deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor cells (MDSC), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs, and indicate that sTNF could be a significant target for cancer prevention and therapy. Cancer Immunol Res; 4(5); 441-51. ©2016 AACR.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sobo-Vujanovic
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lazar
authors.initials: L
authors.lastname: Vujanovic
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Albert B
authors.initials: AB
authors.lastname: DeLeo
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Fernando
authors.initials: F
authors.lastname: Concha-Benavente
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. vujanovicnl@upmc.edu.
authors.forename: Nikola L
authors.initials: NL
authors.lastname: Vujanovic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D017353:Gene Deletion; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology; D008748:Methylcholanthrene; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D008748:Methylcholanthrene