Cells behaving badly: a theoretical model for the Fas/FasL system in tumour immunology

Abstract

One proposed mechanism of tumour escape from immune surveillance is tumour up-regulation of the cell surface ligand FasL, which can lead to apoptosis of Fas receptor (Fas) positive lymphocytes. Based upon this 'counterattack', we have developed a mathematical model involving tumour cell-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. The model predicts that (a) the production of soluble forms of Fas and FasL will lead to the down-regulation of the immune response; (b) matrix metalloproteinase (MMP) inactivation should lead to increased membrane FasL and result in a higher rate of Fas-mediated apoptosis for lymphocytes than for tumour cells. Recent studies on cancer patients lend support for these predictions. The clinical implications are two-fold. Firstly, the use of broad spectrum MMP inhibitors as anti-angiogenic agents may be compromised by their adverse effect on tumour FasL up-regulation. Also, Fas/FasL interactions may have an impact on the outcome of numerous ongoing immunotherapeutic trials since the final common pathway of all these approaches is the transduction of death signals within the tumour cell.

Resistance to Activation-Induced Cell Death and Bystander Cytotoxicity Via the Fas/Fas Ligand Pathway Are Implicated in the Pathogenesis of Cutaneous T Cell Lymphomas

“…Because Fas is a death-inducing receptor and FasL must be tightly controlled at different levels, these may include delivery to the cell surface, cytokine release, as well as cell membrane-associated matrix metalloproteinases (MMP). FasL is cleaved from the cell surface by several members of the MMP family (Kayagaki et al, 1995;Webb et al, 2002). Treatment of activated T cells or tumor cell lines with MMP inhibitors in vitro leads to the accumulation of surface FasL (Strauss et al, 2003).…”

Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

“…Other TDSFs, such as soluble Fas ligand (sFasL) and soluble MHC class I-related chain A gene (sMICA) products, also play important roles in immune evasion, which inhibit Fas-and NKG2D-mediated killing of immune cells (15,16). Another TDSF, soluble phosphatidylserine (sPS), acts as an inducer of an antiinflammatory response to TAMs, resulting in the release of anti-inflammatory mediators, such as IL-10, TGF-h, and PGE 2 , that inhibit an immune response to DCs and T cells (17).…”

Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus

“…In addition, protection against Fas-mediated apoptosis of HBVinfected hepatocytes, involving expression of the transactivating HBV x protein (HBx), may contribute to viral persistence during chronic infection, eventually leading to HCC [Diao et al, 2001;Pan et al, 2001;Su et al, 2001]. In this context, precise roles for sFas and sFasL have yet to be defined although in vitro studies show that both can hinder normal Fas/FasL interactions and thus interfere with apoptosis induction [Cheng et al, 1994;Suda et al, 1997;Webb et al, 2002]. An important observation in this regard concerns the Fas-stimulating capacity of sFasL that is magnitudes lower than that of membrane-bound FasL ].…”