Editors' ChoiceCancer

T cells iron out tumors

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Science Translational Medicine  22 May 2019:
Vol. 11, Issue 493, eaax4878
DOI: 10.1126/scitranslmed.aax4878


T cells induce tumor cell death through ferroptosis.

Tumor-infiltrating T cells play a central role in eliminating solid tumors. T cells can induce tumor cell death through the release of the pore-forming proteins perforin or granzyme, or via interactions with cell surface Fas ligand causing tumor cell apoptosis. Not to be outdone, tumors have evolved sophisticated strategies to prevent T cell–induced demise, including the up-regulation of inhibitory molecules (immune checkpoints) that render the T cells unable to exert their effector function. Immunotherapies that prevent T cell dysfunction, called checkpoint inhibitors, can reenergize cytotoxic T cells with dramatic clinical results.

Wang and colleagues examined the mechanism of CD8+ T cell–mediated tumor cell killing during cancer immunotherapy, focusing on the ability of T cells to regulate tumor cell ferroptosis. Ferroptosis is a relatively newly described form of regulated cell death distinct from apoptosis and necroptosis. During ferroptosis, oxidized lipid species accumulate to lethal concentrations within the cell in an iron-dependent manner. Ferroptosis has been primarily examined in vitro, and it was unclear if antitumor T cells could induce ferroptosis in vivo.

Wang et al. took a number of sophisticated approaches to demonstrate that T cells could induce ferroptosis in vivo and in vitro. Immune checkpoint blockade in animal models reduced tumor growth in a ferroptosis-dependent manner, whereas treatment with the ferroptosis inhibitor liproxstatin-1 attenuated this effect. Mechanistically, tumor cell coculture with the supernatant from activated T cells induced lipid reactive oxygen species (ROS), an indicator of ferroptosis. Effector T cells secrete the proinflammatory cytokine interferon-γ (IFN-γ), and blockade of IFN-γ signaling through neutralizing antibodies or genetic approaches prevented lipid ROS accumulation. Recombinant IFN-γ alone reduced tumor volume in immunodeficient mice, an effect that could be blocked with liproxstatin-1. Further, analysis of gene expression in melanoma patients revealed that patients showing a clinical benefit of immunotherapy expressed gene signatures suggesting active T cell–induced ferroptosis. Although it will be important to conclusively demonstrate that this pathway is active in human cancers, this work suggests that anticancer treatments targeting ferroptosis-associated pathways could yield clinical benefits.

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