Tumor Necrosis Factor alpha (TNF-α) is a major inflammatory cytokine, produced by a wide variety of cell types including macrophages, T lymphocytes endothelial cells and tumor cells. TNF-α is expressed as a membrane-tethered protein (tmTNF-α), cleaved by tumor necrosis factor-α-converting enzyme (TACE) and subsequently released into extracellular space as a soluble TNF-α (sTNF-α). Recent studies from our laboratory and others have shown that low level expression of TNF-α by tumor cells substantially increases tumor growth, vascularity and decreases tumor necrosis, in part by increasing tumor content of a proangiogenic myeloid subtype (Li et al., Cancer Res. 2009, 1;69(1):338-48). To better understand the mechanism by which TNF-α modulates the myeloid phenotype, we generated murine Lewis lung carcinoma (LLC) and B16F10 melanoma tumor cells transduced with retrovirus expression vectors directing modest overexpression of a membrane tethered moiety, tmTNF-α. Heterotopic implantation of tmTNF-α expressing lines resulted in significantly decreased growth than control tumors in both tumor models. Our studies showed that this was not due to effects on the tumor cells themselves but likely due to effects on tumor stroma as the effect of tmTNF-α was lost in TNF-α receptor deficient mice. Further evaluation showed an absence of tumor associated myeloid cells within the tumor, which suggested apoptosis of migrated myeloid cells or inhibition of myeloid recruitment into the tumor environment. There is a significant gap in our knowledge on the mechanism of transmembrane isoform of TNF-α and its potential anti-tumorogenic role. In this study our goal is to identify the mechanism in which tmTNF-α promotes tumor regression and to understand how it modulates host bone marrow derived myeloid cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 448. doi:10.1158/1538-7445.AM2011-448