Cancer Immunotherapy May be Improved by Targeting Ferroptosis

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graphical abstract
This graphical abstract shows how T-cells alter the metabolism of amino acids to cause ferroptosis. [University of Michigan Rogel Cancer Center]

Scientists at the University of Michigan Rogel Cancer Center discovered that a type of cell death known as ferroptosis occurs in tumor cells and plays a role in cancer immunity. The team’s study (“CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy”), published in Nature, suggests the potential of targeting this pathway to improve immunotherapy treatments.

“Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumor microenvironment. CD8+ T cells activated by cancer immunotherapy clear tumors mainly by inducing cell death through perforin–granzyme and Fas–Fas ligand pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide. Although it has been investigated in vitro, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios,” the investigators wrote.

“It is unclear whether, and how, ferroptosis is involved in T-cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and that increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate–cystine antiporter system xc, impairs the uptake of cystine by tumor cells, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis.

“In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumor immunity and induced ferroptosis in tumor cells. Expression of system xc was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8.

“Thus, T cell-promoted tumor ferroptosis is an anti-tumor mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.”

Weiping Zou
Weiping Zou, MD, PhD, University of Michigan.

“Ferroptosis had been defined before but it was not known to be linked to cancer cell death or immune cells. This will open a huge window for scientists to explore,” said senior study author Weiping Zou, MD, PhD, the Charles B. de Nancrede professor of surgery, immunology, biology, and pathology at the University of Michigan.

The researchers, in collaboration with Cayman Chemical, found that when immunotherapy revs up the immune T cells, it then enhances oxidized lipids in the tumor cells that leads to ferroptosis. Increased ferroptosis made immunotherapy treatment more effective at killing the cancer, based on studies in mice and human cancer cells.

Ferroptosis is known to be involved in brain and kidney injuries. This is the first time it’s been linked to immune-mediated cancer cell death, according to the scientists.

In cancer cells, researchers found, the T cells change the metabolism of the amino acids cystine and cysteine, key fuel sources for tumor cells. Working with chemical engineers from the University of Texas at Austin, they engineered an enzyme, cyst(e)inase, to deplete tumor cells of cystine and cysteine. This led to dramatic tumor cell death, which the researchers could reverse or block by inhibiting ferroptosis, explained Zou.

When mice were given the checkpoint inhibitor immunotherapy drug in combination with the ferroptosis sensitizer, the impact on tumor growth was dramatically stronger than with either agent alone. The researchers concluded that the combination of a ferroptosis sensitizer and checkpoint inhibitor creates a strong immune response that fights the tumor by causing ferroptosis. In cancer patients treated with immunotherapy, signs of ferroptosis correlated to the benefits from therapy.

“If ferroptosis is a critical pathway, we may be able to sensitize it to further stimulate immunotherapy or overcome resistance to immunotherapy,” Zou said. “We need to understand this better and work out different mechanisms. Immunotherapy is effective in only about 30% of cancer patients. Our findings provide new insights to understand and explore how to make the immune system work for more patients.”

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