Tumor-induced death of immune cells: its mechanisms and consequences

FasL is a death-inducing as well as pro-inflammatory molecule. The seemingly opposing consequences of Fas/FasL interactions appear to be dependent on the context of the tumor or tissue microenvironment. The term 'contextual' has been coined to describe cellular and molecular events that may be opposing, yet are mediated by the engagement of the same receptor-ligand pair. Because Fas is one of the death-inducing receptors, its ligand is dangerous. Hence, the availability of FasL for cross-linking of the receptor has to be extremely carefully regulated. Different levels of control appear to exist, some involving cell membrane-associated MMPs and others depending on cytokines released from neighboring cells. In tumors, which shape their microenvironment to make it unwelcome to immune effector cells, FasL is used to kill infiltrating cells without damage to the tumor, which develops multiple means of hiding/inhibiting the death pathway. On the other hand, in situations provoking inflammatory responses such as allograft rejection, infection, and tissue necrosis, FasL assumes the role of attractant for inflammatory cells. In these situations, FasL acts in conjunction with other cytokines, and its effects might be modified in the context of unfolding events. When put in the context of biologic interactions that take place at the tumor site, the Fas/FasL pathway emerges as a molecular mechanism, which contributes to immune privilege and tumor escape, but which can also enhance anti-tumor inflammatory responses. FasL, like many cytokines, is pleiotropic. It is also worth bearing in mind that other molecular players, including the other known members of the TNF family, almost certainly participate in establishing immune privilege status of tumors. While a broad body of new information has contributed to clarifying the dual role of FasL in the tumor biology, much remains to be learned about molecular mechanisms that control its effects in the tumor and in normal tissues.