ReviewThe Fas counterattack: cancer as a site of immune privilege
Section snippets
Tumor immune privilege (resistance and counterattack)
The Fas receptor (Fas, APO-1/CD95) and its ligand (FasL, CD95L) are transmembrane proteins of the tumor necrosis factor (TNF) family of receptors and ligands. Engagement of Fas by FasL triggers a cascade of subcellular events that result in programmed cell death (apoptosis). Fas-mediated apoptosis has a fundamental role in immune homeostasis8.
Although FasL was initially thought to be expressed only in cells of the lymphoid/myeloid series including T cells, natural killer (NK) cells, B cells and
Direct counterattack: evidence in vitro and in vivo
The expression of FasL by tumors implies that cancer cells have not only acquired defensive strategies (Fas resistance), but they can also take the offensive (counterattack). This possibility was first suggested by the finding that colon cancer cell lines express FasL and can kill T cells in vitro by inducing Fas-mediated apoptosis13. FasL expression has been demonstrated in a high percentage of resected human colorectal cancers25, melanomas14, hepatocellular cancers15, astrocytomas16 and lung
Systemic consequences of the counterattack
Expression of FasL within a site of immune privilege might have more far-reaching effects than the induction of apoptosis in TILs. From studies in the eye, it appears that an encounter with an antigen within a site of immune privilege has systemic immune consequences, most notably the induction of immune tolerance11, 12, 36. The mechanism of tolerance induction is unclear but might involve interleukin 10 (IL-10)- and transforming growth factor β (TGF-β)-secreting cells similar to those found in
Tumor resistance to Fas-mediated apoptosis
Tumor-cell resistance to Fas-mediated apoptosis is a crucial component of the Fas counterattack. Indeed, it is a prerequisite to FasL expression by tumor cells because, otherwise, autocrine cellular ‘suicide’ or juxtacrine ‘fratricide’ would be expected. It has been shown that within the human intestine, normal colonic epithelial cells express Fas, and are sensitive to Fas-mediated apoptosis44. There is some evidence to suggest that FasL is coexpressed with Fas by normal colonic epithelial
Proinflammatory, antiprivilege and antitumor properties of FasL
Two findings have added a new layer of complexity to the Fas story. First, a polymorphism of FasL has been demonstrated recently, with two allelic forms varying in their capacity to trigger apoptosis in target cells90. This suggests that the aggressiveness of FasL function might vary in different circumstances.
Second, while FasL has been almost universally discussed as a ‘death factor’8, it has emerged that it may, under certain circumstances, have proinflammatory and antitumor activities91, 92
FasL in immune privileged sites: context of expression might determine FasL function
Whether FasL promotes an inflammatory or apoptotic, immune-downregulatory response might be influenced by local microenvironmental factors that vary in different tissues92. These include the presence or absence of a local tissue source of chemokines for neutrophil recruitment, the sensitivity or resistance of the indigenous cells to Fas-mediated apoptosis, the presence or absence of Fas-sensitizing factors such as IFN-γ and the local activity of MMPs able to cleave membrane FasL to soluble FasL
The Fas counterattack as a target for cancer immunotherapy
Disarming the Fas counterattack is a conceptually appealing and exciting potential goal for tumor immunotherapy. Restoration of tumor cell sensitivity to Fas or blockade of expression or function of FasL on the tumor cell will abrogate the Fas counterattack. Sensitivity to Fas has been restored to various cancer cell lines by transfection of several cDNAs encoding components involved in the signal transduction cascade, including Fas itself114, caspase 1 (Ref. 58), Bax (Ref. 76), HCP (Ref. 78)
Conclusion
The clinical importance of the Fas counterattack in vivo is only beginning to emerge, and whether the immune privileged status of some human tumors is as important as that described in the eye remains to be shown. For now, the counterattack model represents an exciting new avenue of research in tumor immunology. Understanding the basis of Fas resistance and counterattack will be important for effective cancer management. Disarming the Fas counterattack might even offer a potential therapeutic
Acknowledgements
The authors’ research is supported by the Health Research Board of Ireland, Forbairt Ireland, and the Cancer Research Appeal Mercy Hospital.
References (118)
- et al.
Immunol. Today
(1993) - et al.
Immunol. Today
(1997) Cell
(1997)- et al.
Immunol. Today
(1997) - et al.
Cell. Immunol.
(1995) - et al.
Cell
(1996) - et al.
Immunity
(1996) Immunol. Today
(1997)- et al.
Gastroenterology
(1997) - et al.
Blood
(1995)
Cancer Lett.
Cell
J. Biol. Chem.
J. Biol. Chem.
Cell
Biochem. Biophys. Res. Commun.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Immunity
J. Biol. Chem.
Immunity
J. Biol. Chem.
J. Biol. Chem.
Immunity
Adv. Cancer Res.
Annu. Rev. Immunol.
Curr. Opin. Immunol.
Mol. Med. Today
J. Immunol.
J. Immunol.
Science
Nature
J. Clin. Immunol.
J. Exp. Med.
Science
Nat. Med.
J. Clin. Invest.
Cancer Res.
Proc. Natl. Acad. Sci. U. S. A.
J. Immunol.
Mol. Med.
J. Immunol.
Nature
J. Immunol.
J. Pathol.
Eur. J. Immunol.
J. Immunol.
J. Immunol.
Cancer Res.
Cited by (216)
Hopf bifurcation without parameters in deterministic and stochastic modeling of cancer virotherapy, part II
2022, Journal of Mathematical Analysis and ApplicationsCitation Excerpt :It is well known that there exist periodic solutions or interactions in predator-prey systems when the system parameters satisfy some conditions. We also know that immune clearance rates are not fixed constants and they change according to on-site immune cell density and cellular signals [8,21]. This gives some possibilities for parameter changes in viral therapy.
Hopf bifurcation without parameters in deterministic and stochastic modeling of cancer virotherapy, part I
2022, Journal of Mathematical Analysis and ApplicationsChallenges and future perspectives of T cell immunotherapy in cancer
2015, Immunology LettersDecoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells
2015, Biochemical and Biophysical Research CommunicationsRecent advances on the role of tumor exosomes in immunosuppression and disease progression
2012, Seminars in Cancer BiologyHuman matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes
2012, Molecular Aspects of Medicine