Membrane versus Soluble Isoforms of TNF-α Exert Opposing Effects on Tumor Growth and Survival of Tumor-Associated Myeloid Cells

TNFα, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNFα can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNFα) or a soluble 17-kDa cytokine (sTNFα), the vast majority of published studies have only investigated the biological effects of the soluble form. We demonstrate for the first time that membrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNFα, generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNFα. The lack of myeloid cells was due to a direct effect of mTNFα on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human NSCLCs expressed varying levels of both soluble and membrane TNFα, and gene expression patterns favoring mTNFα were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNFα isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNFα inhibitors, which can block both TNFα isoforms.