CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy

Abstract

Summary Cancer immunotherapy restores and/or enhances effector function of CD8+ T cells in the tumor microenvironment1,2. CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation5,6. Although it was mechanistically illuminated in vitro7,8, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios9,10. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, interferon gamma (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 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.

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…Other Molecular Indicators : In addition to the molecules discussed above, ferroptosis process can also be monitored by detection of GSH depletion, release of glutamate, and cystine uptake . Proteins involved in ferroptosis, such as SLC7A11 can be characterized by immunofluorescence staining .…”

“…In addition to the combination of multiple forms of RCDs for eradicating malignancies, the non‐apoptotic nature of ferroptosis also inspired research on the immunostimulatory property of ferroptosis inducers . One of the pioneer work described a biomimetic magnetosome nanoparticle (Pa‐M/Ti‐NCs) for ferroptosis/immunomodulation synergistic cancer therapy ( Figure ).…”

“…Due to its non‐apoptotic nature, ferroptosis‐based cancer therapy is expected to bypass the drawbacks of traditional therapeutics mediated by apoptosis pathways. Recently, ferroptosis has also been proved to be involved in cancer immunotherapy, where T cells and interferon‐gamma (IFN‐γ) sensitize tumor cells to ferroptosis . All of these highlight the promising role of ferroptosis induction in cancer treatment.…”

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma

“…We also observed recurrent dysregulation of ferritin and HSP90-related genes, suggestive of an enhanced acute-phase protein reaction, iron loading and molecular stress in the context of chromosome 7 gain and immunotherapy failure. Iron availability is known to influence tumor cell survival and the function of numerous immune cell types including T cells; however, these competing outcomes have been poorly studied in solid tumors such as melanoma 39,40 . Nevertheless, a potential role for immunosuppressive neutrophil phenotypes and iron trafficking within the TME warrants further evaluation.…”

Systematic analysis of aberrances of ferroptosis reveals its potential functional roles in cancer

“…Recently, Wang et al reported that CD8+ T cells could promote tumor ferroptosis during cancer immunotherapy treatment (Wang et al, 2019). Thus, ferroptosis might play important roles during cancer progression and treatment, and a systematic study for ferroptosis and its aberrances across cancers will be helpful.…”