Abstract
BackgroundSub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity. Previous studies indicate that cancer cells respond to radiation by up-regulating surface expression of death receptors, cell adhesion molecules and tumor-associated antigens (TAA). However, there is limited information available regarding how T cells themselves are altered following these interactions with irradiated tumor cells.MethodsHere, several human colorectal tumor cell lines were exposed to radiation (0–10 Gy) in vitro and changes in the expression of molecules costimulatory to effector T cells (4-1BBL, OX-40L, CD70, ICOSL) were examined by flow cytometry. T cell effector function was assessed to determine if changes in these proteins were directly related to the changes in T cell function.ResultsWe found OX-40L and 4-1BBL to be the most consistently upregulated proteins on the surface of colorectal tumor cells post-IR while ICOSL and CD70 remained largely unaltered. Expression of these gene products correlated with enhanced killing of irradiated human colorectal tumor cells by TAA-specific T-cells. Importantly, blocking of both OX-40L and 4-1BBL reversed radiation-enhanced T-cell killing of human tumor targets as well as T-cell survival and activation.ConclusionsOverall, results of this study suggest that, beyond simply rendering tumor cells more sensitive to immune attack, radiation can be used to specifically modulate expression of genes that directly stimulate effector T cell activity.
Highlights
Sub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity
Sub‐lethal irradiation of colorectal carcinoma cell lines does not modulate all T cell stimulatory molecules the same There are a number of proteins that, when expressed by target cells, can contribute to enhanced local activity of CD8+ cytolytic T cells through increased activation or survival
We previously reported increased expression of OX-40L and 4-1BBL in two colorectal tumor cell lines [44] and wanted to evaluate if the expression of other co-stimulators of CD8+ effector cells was changed in irradiated colorectal tumor cells
Summary
Sub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity. There is limited information available regarding how T cells themselves are altered following these interactions with irradi‐ ated tumor cells. Many cancer patients undergo RT during their course of illness tumor cells acquire mutations during development that inhibit cell death by radiation [1]. Radiation has significant dose limiting toxicities when used as a definitive therapy or in sensitive tissues such as the colon [3, 4]. Cancer immunotherapy (CIT) is emerging as an attractive therapeutic option and many standard cancer therapies, such as chemotherapy and radiation, rely on induction of functional immune cells for efficacy [5, 6]. Understanding the role of RT in tumor immunity will
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