IFN-gamma+ 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)-gamma+ 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-gamma or by blocking the inducible isoform of nitric oxide synthase, thus delineating the immune-tumor cell interaction through the IFN-gamma secretion pathway. Reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorter data in agreement detected downregulation of the IFN-gamma gene by hypoxia, which caused IFN-gamma 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.
Radiotherapie, Oncologisch Centrum, UZ Brussel, Brussels, Belgium. mark.deridder@uzbrussel.be
Mark
M
De Ridder
Heng
H
Jiang
Gretel
G
Van Esch
Kalun
K
Law
Christinne
C
Monsaert
Dirk L
DL
Van den Berge
Dirk
D
Verellen
Valeri N
VN
Verovski
Guy A
GA
Storme
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects*; D015687:Cell Hypoxia / Q000276:immunology / Q000528:radiation effects; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D007113:Immunity, Innate / Q000276:immunology* / Q000528:radiation effects; D007371:Interferon-gamma / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011829:Radiation Dosage
D007371:Interferon-gamma