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

// Priscilla S. Simon 1,4,6 , Kankana Bardhan 1 , May R. Chen 1 , Amy V. Paschall 1,4,6 , Chunwan Lu 1,6 , Roni J. Bollag 4 , Feng-Chong Kong 2,4 , JianYue Jin 2,4 , Feng-Ming Kong 2,4 , Jennifer L. Waller 3 , Raphael E. Pollock 5 and Kebin Liu 1,4,6 1 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA 2 Radiation Oncology, Medical College of Georgia, Augusta, GA, USA 3 Biostatistics and Epidemiology, Medical College of Georgia, Augusta, GA, USA 4 Cancer Center, Georgia Regents University, Augusta, GA, USA 5 Ohio State University Medical Center, Columbia, OH, USA 6 Charlie Norwood VA Medical Center, Augusta, GA, USA Correspondence to: Kebin Liu, email: // Keywords : NF-κB, radiation, TNFα, cytotoxic T lymphocyte, Smac mimetic Received : December 28, 2015 Accepted : February 28, 2016 Published : March 21, 2016 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.