Inhibition of Soluble Tumor Necrosis Factor Prevents
Chemically Induced Carcinogenesis in Mice.
Sobo-Vujanovic A1, Vujanovic L2, DeLeo AB3, Concha-Benavente
F4, Ferris RL4, Lin Y5, Vujanovic NL6.
1. University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania.
2. University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania. Department of Medicine, University of Pittsburgh, Pittsburgh,
Pennsylvania.
3. University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania. Department of Pathology, University of Pittsburgh, Pittsburgh,
Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh,
Pennsylvania.
4. University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh,
Pennsylvania. Department of Otolaryngology, University of Pittsburgh,
Pittsburgh, Pennsylvania.
5. University of Pittsburgh Cancer Institute, Pittsburgh,
Pennsylvania. Department of Biostatistics, University of Pittsburgh,
Pittsburgh, Pennsylvania.
6. 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.
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.
Cancer Immunol Res. 2016 May;4(5):441-51. doi: 10.1158/2326-6066.CIR-15-0104.
Epub 2016 Feb 19.
Md.
PhD. Fernando Concha. Ex-miembro del GII
