Amanda Sell

The potential radiation protective effect of orgotein, a metalloprotein with superoxide dismutase activity, was investigated in L1A2 tumour cells in vitro, jejunal crypt cells and C3H mouse mammary carcinoma in vivo. No effect of orgotein, given either 2 hours before irradiation or 30 min after, was observed compared to the effect of irradiation alone. Thus, it was concluded that orgotein did not influence the primary radiation response in air in mammalian cells.

Abstract Cytotoxic T cells recognize specific antigens expressed on tumor cells and mediate tumor cell apoptosis mainly through perforin–granzyme-mediated and FAS-mediated pathways. Ferroptosis is a recently discovered form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. The potential contribution of CD8+ T cell-mediated cytotoxic activity and immunotherapy to tumor ferroptosis remains unknown. Here, we find that immunotherapy-activated CD8+ T cells sensitize tumor cell ferroptosis. Mechanistically, IFNγ released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc−, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Expression of glutamate-cystine antiporter system xc− is negatively associated with CD8+ T cell signature, IFNγ expression, and cancer patient outcome. Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.