Tumor necrosis factor (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, strikingly 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, temporarily blocked, whereas gene-deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA enhanced circulating IL-1beta levels, and accumulation of myeloid-derived suppressor-cells (MDSCs), STAT3 phosphorylation and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL-1alpha and increased the essential immunoregulatory cytokines IL-1beta IL-12p70 and IL-17 in the peripheral blood of MCA-injected mice. Furthermore, DN-TNF treatment, TNFR2-Fc treatment and/or gene deletion of TNF or TNFR1, but not of TNFR2, prevented MDSC accumulation, STAT3 phosphorylation and immunosuppression in MCA-injected mice. These novel 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.
- Received April 14, 2015.
- Revision received February 16, 2016.
- Accepted February 16, 2016.
- Copyright © 2016, American Association for Cancer Research.