title: NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression.
abstract: Radiation modulates both tumor cells and immune cells in the tumor microenvironment to exert its anti-tumor activity; however, the molecular connection between tumor cells and immune cells that mediates radiation-exerted tumor suppression activity in the tumor microenvironment is largely unknown. We report here that radiation induces rapid activation of the p65/p50 and p50/p50 NF-κB complexes in human soft tissue sarcoma (STS) cells. Radiation-activated p65/p50 and p50/p50 bind to the TNFα promoter to activate its transcription in STS cells. Radiation-induced TNFα induces tumor cell death in an autocrine manner. A sublethal dose of Smac mimetic BV6 induces cIAP1 and cIAP2 degradation to increase tumor cell sensitivity to radiation-induced cell death in vitro and to enhance radiation-mediated suppression of STS xenografts in vivo. Inhibition of caspases, RIP1, or RIP3 blocks radiation/TNFα-induced cell death, whereas inhibition of RIP1 blocks TNFα-induced caspase activation, suggesting that caspases and RIP1 act sequentially to mediate the non-compensatory cell death pathways. Furthermore, we determined in a syngeneic sarcoma mouse model that radiation up-regulates IRF3, IFNβ, and the T cell chemokines CCL2 and CCL5 in the tumor microenvironment, which are associated with activation and increased infiltration of Th1/Tc1 T cells in the tumor microenvironment. Moreover, tumor-infiltrating T cells are in their active form since both the perforin and FasL pathways are activated in irradiated tumor tissues. Consequently, combined BV6 and radiation completely suppressed tumor growth in vivo. Therefore, radiation-induced NF-κB functions as a molecular link between tumor cells and immune cells in the tumor microenvironment for radiation-mediated tumor suppression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Simon
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.
authors.forename: Kankana
authors.initials: K
authors.lastname: Bardhan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.
authors.forename: May R
authors.initials: MR
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Paschall
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Chunwan
authors.initials: C
authors.lastname: Lu
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Roni J
authors.initials: RJ
authors.lastname: Bollag
authors.affiliation: Radiation Oncology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Feng-Chong
authors.initials: FC
authors.lastname: Kong
authors.affiliation: Radiation Oncology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: JianYue
authors.initials: J
authors.lastname: Jin
authors.affiliation: Radiation Oncology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Kong
authors.affiliation: Biostatistics and Epidemiology, Medical College of Georgia, Augusta, GA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
authors.affiliation: Ohio State University Medical Center, Columbia, OH, USA.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA.|Cancer Center, Georgia Regents University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005720:Gamma Rays; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D012509:Sarcoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology* / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha
keywords: NF-κB; Smac mimetic; TNFα; cytotoxic T lymphocyte; radiation