The Fas counterattack: cancer as a site of immune privilege

doi:10.1016/S0167-5699(98)01382-6

Immunology Today

Volume 20, Issue 1, 1 January 1999, Pages 46-52

Immunology Today

https://doi.org/10.1016/S0167-5699(98)01382-6 Get rights and content

Abstract

Resistance to apoptosis through the Fas receptor pathway coupled with expression of the Fas ligand might enable many cancers to deliver a pre-emptive strike or counterattack against the immune system. Therapeutic exploitation of this has exciting potential, but now seems more complex and hazardous than was first evident.

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.

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ReviewThe Fas counterattack: cancer as a site of immune privilege

Abstract

Section snippets

Tumor immune privilege (resistance and counterattack)

Direct counterattack: evidence in vitro and in vivo

Systemic consequences of the counterattack

Tumor resistance to Fas-mediated apoptosis

Proinflammatory, antiprivilege and antitumor properties of FasL

FasL in immune privileged sites: context of expression might determine FasL function

The Fas counterattack as a target for cancer immunotherapy

Conclusion

Acknowledgements

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Review
The Fas counterattack: cancer as a site of immune privilege