Unexpected Pathway May Improve Patient Response to Immunotherapy

Unexpected Pathway May Improve Patient Response to Immunotherapy

ferroptosisA new study published in Nature revealed that a type of cell death called ferroptosis could allow for a new pathway to be targeted in cancer immunotherapies. The team is based at the University of Michigan Rogel Cancer Center, led by Weiping Zou, MD, the Charles B. de Nancrede Professor of Surgery, Immunology, Biology and Pathology at U-M.

According to Zou, “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.

The team discovered that when immunotherapy treatments stimulate the immune T-cells, oxidized lipids in the tumor cells are then bolstered to create ferroptosis. In both mouse and human studies, increased ferroptosis also allowed immunotherapy treatment to kill cancer cells more effectively.

What is ferroptosis?

ferroptosisFerroptosis is a kind of cell death, but it is different from the well-known apoptosis. Ferroptosis is not studied very often and scientists know little about it, other than that it requires iron. Although it’s commonly associated with brain and kidney injuries, this research marks the first time it’s been connected with immune-mediated cancer cell death.

The research showed that in cancer cells, T-cells alter the metabolism of the amino acids cystine and cysteine, which are important fuel sources for tumors cells. In collaboration with chemical engineers from the University of Texas at Austin, the team created an enzyme that would rid tumor cells of cystine and cysteine. As a result, tumor cell death occurred at a significant rate, and the researchers could inhibit this cell death by blocking ferroptosis.

ferroptosisThe team then administered the checkpoint inhibitor drugs with ferroptosis sensitizer to mouse models. The results showed that the effect on tumor growth was significantly stronger than with either agent given alone. The team thus believes that the combination of a ferroptosis sensitizer and checkpoint inhibitor can allow for a strong immune response that induces ferroptosis and attacks the tumor. Cancer patients who were being treated with immunotherapy showed that any signs of ferroptosis were also linked to better therapy response.

Zou said that “if ferroptosis is a critical pathway, [they] may be able to sensitize it to further stimulate immunotherapy or overcome resistance to immunotherapy.”

But the study is still in its early phases, and the team needs to better understand the process so they can come up with different ways to use it. There are many unanswered questions, and the team will continue to explore the findings before the treatment moves forward.