Forward and Reverse Signaling Mediated by Transmembrane Tumor Necrosis Factor-Alpha and TNF Receptor 2: Potential Roles in an Immunosuppressive Tumor Microenvironment

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic inflammatory cytokine produced mainly by activated macrophages, lymphocytes and other cell types. Two distinct forms of TNF-alpha have been identified: soluble TNF-alpha (sTNF-alpha) and transmembrane TNF-alpha (mTNF-alpha). mTNF-alpha, which is the precursor of sTNF-alpha, can be cleaved by the TNF-alpha converting enzyme (TACE) and is released as sTNF-alpha. sTNF-alpha binds primarily to TNF receptor 1 (TNFR1) and plays an important role in the inflammatory immune response, whereas mTNF-alpha interacts primarily with TNF receptor 2 (TNFR2) and mediates the promotion of cellular proliferation and survival and other biological effects. It has been reported that the interaction between mTNF-alpha and TNFR2 induces bi-directional (forward and reverse) signaling in both mTNF-alpha-and TNFR2-expressing cells. Increasing evidence shows that the forward and reverse signaling mediated by mTNF-alpha and TNFR2 might play a significant role in the tumor microenvironment. In this review, the role of the crosstalk between mTNF-alpha and TNFR2 in the tumor microenvironment will be discussed.