Dose-dependent enhancement of T-lymphocyte priming and CTL lysis following ionizing radiation in an engineered model of oral cancer. (August 2017)

• Record Type: Journal Article
• Authors: Morisada, Megan; Moore, Ellen C.; Hodge, Rachel; Friedman, Jay; Cash, Harrison A.; Hodge, James W.; Mitchell, James B.; Allen, Clint T.
• Is Part Of: Oral oncology. Volume 71(2017)
• Page Start: 87
• Page End: 94
• Publication Date: 2017-08
• Subjects: Radiation -- Immunity -- Tumor microenvironment -- T-lymphocyte priming -- Cytotoxic T-lymphocyte; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2017.06.005
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Ionizing radiation (IR) induces apoptosis in a dose-dependent fashion. 8 Gy IR induces release of tumor antigen to a greater degree than 2 Gy. 8 Gy IR induces T-cell priming in vitro to a greater degree than 2 Gy. 8 Gy IR induces T-cell priming in peripheral and tumor compartments in vivo . Higher single doses of IR should be considered when combining IR and immunotherapy. Abstract: Objectives: Determine if direct tumor cell cytotoxicity, antigen release, and susceptibility to T-lymphocyte killing following radiation treatment is dose-dependent. Materials and methods: Mouse oral cancer cells were engineered to express full-length ovalbumin as a model antigen. Tumor antigen release with uptake and cross presentation of antigen by antigen presenting cells with subsequent priming and expansion of antigen-specific T-lymphocytes following radiation was modeled in vitro and in vivo . T-lymphocyte mediated killing was measured following radiation treatment using a novel impedance-based cytotoxicity assay. Results: Radiation treatment induced dose-dependent induction of executioner caspase activity and apoptosis in MOC1 cells. In vitro modeling of antigen release and T-lymphocyte priming demonstrated enhanced proliferation of OT-1 T-lymphocytes with 8 Gy treatment of MOC1ova cells compared to 2 Gy. This was validated in vivo following treatment of established MOC1ova tumors and adoptive transfer of antigen-specific T-lymphocytes. Using a novel impedance–based cytotoxicity assay, 8 Gy enhanced tumor cell susceptibility to T-lymphocyte killing to a greater degree than 2 Gy. Conclusion: In the context of using clinically-relevant doses of radiation treatment as an adjuvant for immunotherapy, 8 Gy is superior to 2 Gy for induction of antigen-specific immune responses and enhancing tumor cell susceptibility to T-lymphocyte killing. These findings have significant implications for the design of trials combining radiation and immunotherapy.