Research suggests that the cell death mechanism known as ferroptosis boosts the effectiveness of checkpoint inhibitors. The work indicates that CD8+ T cells trigger ferroptosis in cancer cells by releasing IFNγ, which then disrupts uptake of the amino acid cystine. Further experiments in mice with ovarian tumors established that T cells can induce ferroptosis in vivo.

Checkpoint inhibitors induce CD8+ T cells to trigger apoptosis of tumor cells. The drugs also spur the T cells to kill through a little-known form of cell death called ferroptosis, a study shows. The discovery suggests that agents that induce ferroptosis, some of which are under development, might boost the effectiveness of immunotherapy.

Ferroptosis involves iron-dependent accumulation of oxidized lipids. Although researchers are still trying to pin down the precise role of ferroptosis, some evidence suggests that it helps defend against cancer. For example, the tumor suppressor TP53 stimulates ferroptosis in some cancer cells in vitro, scientists have reported. Weiping Zou, MD, PhD, of the University of Michigan School of Medicine in Ann Arbor, and colleagues wondered whether ferroptosis enhanced the antitumor activity of checkpoint blockade.

Studying mice with melanomas or ovarian tumors, researchers found that a PD-L1 inhibitor reduced tumor growth and increased oxidized lipids in cancer cells, suggesting that the drug promotes ferroptosis. The scientists tested tumor-killing CD8+ T cells in vitro and found that the cells spur ferroptosis by releasing IFNγ. IFNγ, in turn, curbs expression of SLC3A2 and SLC7A11, two components of a system that normally enables cells to import the amino acid cystine. Knocking down either SLC3A2 or SLC7A11 sensitized tumor cells to a ferroptosis inducer.

Zou's team also uncovered evidence that ferroptosis is active in people with cancer. Analyzing data from The Cancer Genome Atlas, they discovered that low expression of SLC3A2 and high expression of IFNγ were associated with longer survival in patients with melanoma. Similarly, in tissue from patients before and after treatment with the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb): SLC3A2 expression fell and IFNγ expression rose in those who responded.

To determine whether a ferroptosis-stimulating molecule could increase the effectiveness of checkpoint inhibitors, the team gave mice with ovarian tumors an anti–PD-L1 drug; an enzyme known as cyst(e)inase that breaks down cystine and induces ferroptosis; or both. After 35 days, the tumor load in mice that received the two drugs was over 50% lower than in mice that received either treatment alone. Zou says that the results suggest that “we can empower T cells to kill tumor cells” by spurring ferroptosis, adding that some of his collaborators are working to develop a cyst(e)inase drug.

“It's the first paper to show that immunotherapy drugs can induce this kind of cell death,” says Boyi Gan, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who wasn't connected to the study. “Overall, I think the evidence is quite convincing.” The results also suggest a way to overcome immunotherapy resistance, says Spencer Gibson, PhD, of the University of Manitoba in Winnipeg, Canada, who also wasn't connected to the study. “If you can activate ferroptosis, you may short-circuit these resistance pathways.”

But Marcus Conrad, PhD, of the Helmholtz Zentrum München in Germany, cautions that more work needs to be done before clinical testing of ferroptosis-stimulating molecules can begin. “Ferroptosis-inducing agents that reliably work in vivo still have to be developed, as most of the [existing] ferroptosis-inducing agents are either metabolically unstable or target [signaling] nodes that can be bypassed in vivo.” –Mitch Leslie

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.