• Function of TNF Death Receptors in Apoptosis and Cancer Immune Surveillance

      Hu, Xiaolin; Department of Biochemistry and Molecular Biology (2012)
      Tumor necrosis factor receptor (TNFR) is a group of death receptors that can mediate extrinsic apoptosis in target cells upon specific ligand engagement. Members of the TNFR super family play a pivotal role in cytotoxic T cell-mediated immune surveillance and immune regulation. However, cancer cells can acquire apoptosis resistance through down-regulating surface TNFR level or alteration of key mediators in the TNFR signaling pathway so that cancer cells can evade TNFR-mediated and immune cell-based cytotoxicity. Therefore, understanding the underlying mechanism of cancer resistance to TNFR-mediated apoptosis will provide the basis for identifying specific molecular targets and effecient cancer therapy. In this study, we discovered that chronic myelogeneous leukemia (CML) cells use DNA methylation to down-regulate IRF8, a tumor suppressor gene, to acquire apoptosis resistance to Fas-mediated apoptosis. More importantly, we showed that acid ceramidase is a transcription target of IRF8. Restoration of IRF8 or inhibition of acid ceramidase can re-sensitize CML cells to FasL-induced apoptosis in vitro. Furthermore, such manipulation can prolong mouse survival in vivo. While targeting Fas-mediated apoptosis is one strategy to restore immune cell-mediated surveillance, targeting other TNFR members sheds light on monoclonal antibody (mAb) based therapy. We demonstrated that LTβR, as a member of the death receptor super family, could function in cancer immune surveillance through mediating tumor cell apoptosis in sarcoma, colon and mammary carcinoma in a caspase dependent way. Because LTR is selectively up-regulated on cancer cells, it could potentially be a good target for cancer-selective killing. Targeting the TNFR pathway might not only eliminate tumors, but it may also emerge as a promising target to eliminate myeloid derived suppressor cells that accumulate in the peripheral blood under neoplastic conditions. We demonstrated that tumor induced myeloid derived suppressor cells (MDSC) were more resistant to apoptosis than the cells with the same phenotype in tumor free mice. We also identified that up-regulation of Bcl-xL is one of the mechanisms responsible for apoptosis resistance in tumor induced MDSC and that inhibiting Bcl-xL by BH3 mimetics could greately sensitize MDSC to FasL induced apoptosis.