IFN-γ+ CD8+ T Lymphocytes: Possible Link Between Immune and Radiation Responses in Tumor-Relevant Hypoxia

Activated T lymphocytes are known to kill tumor cells by triggering cytolytic mechanisms; however, their ability to enhance radiation responses remains unclear. This study examined the radiosensitizing potential of mouse CD8+ T cells, obtained by T-cell-tailored expansion and immunomagnetic purification. Activated CD8+ T cells displayed an interferon (IFN)-γ+ phenotype and enhanced by 1.8-fold the radiosensitivity of EMT-6 tumor cells in 1% oxygen, which modeled tumor-relevant hypoxia. Radiosensitization was counteracted by neutralizing IFN-γ or by blocking the inducible isoform of nitric oxide synthase, thus delineating the immune-tumor cell interaction through the IFN-γ secretion pathway. Reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorter data in agreement detected downregulation of the IFN-γ gene by hypoxia, which caused IFN-γ deficiency next to radioresistance. Therefore, immune and radiation responses are likely to be allied in the hypoxic tumor microenvironment, and CD8+ T cells may bridge immunostimulatory and radiosensitizing strategies.