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

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

Oral Oncol. 2017 Aug;71:87-94

Authors: Morisada M, Moore EC, Hodge R, Friedman J, Cash HA, Hodge JW, Mitchell JB, Allen CT

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 8Gy treatment of MOC1ova cells compared to 2Gy. 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, 8Gy enhanced tumor cell susceptibility to T-lymphocyte killing to a greater degree than 2Gy.
CONCLUSION: In the context of using clinically-relevant doses of radiation treatment as an adjuvant for immunotherapy, 8Gy is superior to 2Gy 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.

PMID: 28688697 [PubMed - in process]

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