title: Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack.
abstract: Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8⁺ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.
authors.affiliation: Department of Molecular Biology and Genetics, Gaziosmanpasa University, 60250 Tokat, Turkey. ercan.cacan@gop.edu.tr.
authors.forename: Ercan
authors.initials: E
authors.lastname: Cacan
authors.affiliation: Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA 30303, USA. aspring1@gsu.edu.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Spring
authors.affiliation: Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA 30303, USA. akumari1@student.gsu.edu.
authors.forename: Anita
authors.initials: A
authors.lastname: Kumari
authors.affiliation: Department of Clinical Research and Immunology, American Cancer Society, 250 Williams St, Atlanta, GA 30303, USA. susanna.greer@cancer.org.
authors.forename: Susanna F
authors.initials: SF
authors.lastname: Greer
authors.affiliation: Department of Biology, Georgia State University, 161 Jesse Hill Jr. Dr, Atlanta, GA 30303, USA. cgarnettbenson@gsu.edu.
authors.forename: Charlie
authors.initials: C
authors.lastname: Garnett-Benson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000069286:Bortezomib / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011839:Radiation, Ionizing; D053218:Receptors, Death Domain / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D053218:Receptors, Death Domain; D000069286:Bortezomib
keywords: anti-tumor immunity; death receptors; proteasome; radiation