TNF Family Ligands

In addition to the classical killing mechanism, NK cells uses several other proteins to induce tumor apoptosis mediated by caspase activation [95]. NK cells were shown to express the TNF, lymphotoxin (LT)-a, LT-6, FasL, CD27L, CD30L, OX40L, 4-1BBL, and TRAIL [95]. However, several examples show these mechanisms are also used by the tumors to counterattack the immune cells. For example, FasL expression was significantly higher on NK cells of the TILs population derived from Hepatocellular carcinoma patients [96]. However, activated lym phocytes in general, and NK cells in particular also express the Fas receptor itself. Thus, the FasL expression on tumors might leads to the induction of apoptosis in the activated NK and T cells [97]. While Fas is expressed in most tissues, and is induced by IFNg and TNFa, tumor cells are frequently found to be less sensitive to Fas-induced apoptosis. Reduced Fas expression was reported to result from p53 mutation [98], or from AKT signaling in hypoxic tumors [99].

Triggering of the TNFa pathway results in apoptotosis and death of various tumor cells [94]. However, in contrast to its intended antitumor effect, sustained exposure to TNFa was demonstrated to cause progression of tumors in vivo, through the activation of the NF-kB pathway [100]. Moreover, it was recently demonstrated that in melanoma cells treated with BRAF-inhibitors the TNFa specifically prevent apoptosis through NF-kB activation [101] . These examples of TNFa potential pro-tumor effect highlight the risk of this killing pathway.

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