The Janus Face of Death Receptor Signaling during Tumor Immunoediting

Abstract

Cancer immune surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognized by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumor cells by expressing death ligand cytokines of the tumor necrosis factor ligand family. However, some tumor cells can escape immune elimination and progress. Acquisition of resistance to the death ligand-induced apoptotic pathway can be obtained through cleavage of effector cell expressed death ligands into a poorly active form, mutations or silencing of the death receptors, or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/dysfunctional death ligand signaling curbs its cytotoxicity. Moreover, DRs can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signaling does not only give a passive resistance against cell death but actively drives tumor cell motility, invasion, and contributes to consequent metastasis. This dual contribution of the death receptor signaling in both the early, elimination phase, and then in the late, escape phase of the tumor immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumor-eliminating immune effector function even in the absence of activation of the immune system against the tumor. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.

CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30− Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions

“…While eradicating CD30 þ EC cells via perforin/granzyme B-mediated mechanisms, CD30.CAR T cells also upregulate FasL and eliminate surrounding CD30tumor cells, if they express the CD95 molecule, via caspase 3 activation. The Fas/FasL pathway is relevant in tumor immunology (41), and Fas agonist mAbs have been developed to activate the apoptotic cascade in tumor cells (42). However, this strategy was not clinically developed due to the systemic toxicities caused by the nonselective targeting of CD95-expressing cells in normal tissues, such as hepatocytes (43).…”

“…Although our data indicate that the Fas/FasL pathway is critical for CD30.CAR T cells to eliminate surrounding antigen neg tumor cells, tumor cells can still escape immune cell targeting due to tumor-associated dysfunctions of the Fas/FasL pathway. For example, tumor cells can downregulate Fas by competition of Fas isoforms or impairment of surface Fas expression (41) or, in the case of EC, develop nonfunctional Fas mutations (44). In the examples of tumor escape due to alternatively spliced isoforms (5) or antigen loss (6) after CAR T-cell therapy, it is also plausible that endogenous Fas is dysfunctional in these tumors and thus CAR T cells are unable to eliminate antigen neg tumor cells using the Fas/FasL mechanism.…”

Immune ligands for cytotoxic T Lymphocytes CTLS in cancer stem cells CSCS

“…It is worth mentioning, at this point, that other members of the TNFRSF, TNFRSF1 (p55), Fas (TNFRSF6), DR4 (TNFRSF10A) and DR5 (TNFRSF10B) are the main effectors of the immune cytotoxicity (together with the granzyme/ perforin system) after recognition of tumor cells by CTLs (39). These members, that are effectors of the immune execution, are regulated in the intra-cellular level and under certain conditions may promote cell survival through NF-κB activation and cell motility instead of cell death.…”

Vaccination in the immunotherapy of glioblastoma

“…Immunoediting refers to the remodeling of tumor cells to promote their motions, invasions and metastases while eliminating by the immune system. 123,124 The relationship between tumors and the immune system is believed to consist of the following three phases: during the 'elimination phase', the tumor cells are killed by the immune system; during the 'equilibrium phase', there is a state of equilibrium between the tumor cells and the immune system; and during the 'escape phase', the tumor cells evade the surveillance of the immune system and eventually form tumors. 123,124 Immunoediting is one of the greatest obstacle in tumor immunotherapy.…”