Researchers find new target to improve response to cancer immunotherapy

New discoveries suggest that an unexpected way to kill cancer cells could make cancer treatment the most in demand, immunotherapy, more effective.

Researchers at the University of Michigan Rogel Cancer Center have been studying a type of poorly understood cell death called ferroptosis. They discovered that ferroptosis occurs in tumor cells and plays a role in immunity against cancer, suggesting the potential for targeting this pathway to improve immunotherapy treatments. The study is published in Nature.

"The ferroptosis had already been defined, but it was not known to be badociated with the death of cancer cells or immune cells.This will open a huge window to the exploration of scientists," says lead researcher Weiping Zou, MD, Ph.D., Charles B. de Nancrede Professor of Surgery, Immunology, Biology and Pathology at the University of Michigan.

Researchers, in collaboration with Cayman Chemical, found that when immunotherapy strengthened immune T cells, it then enhanced oxidized lipids in tumor cells leading to ferroptosis. Increased ferroptosis has made the immunotherapy treatment more effective at killing cancer, based on studies conducted on mouse and human cancer cells.

Ferroptosis is a form of cell death distinct from apoptosis better known and well studied. It depends on the iron, but we do not understand much about it. It is known that she is involved in brain and kidney damage. This is the first time that it is badociated with the death of immune-mediated cancer cells.

The researchers found that in cancer cells, T cells alter the amino acid metabolism, cystine and cysteine, essential fuel sources for tumor cells. Working with chemical engineers from the University of Texas at Austin, they developed an enzyme intended to eliminate tumor cells from cystine and cysteine. This led to a dramatic death of tumor cells, which the researchers were able to reverse or block by inhibiting ferroptosis.

When the mice received the control point inhibitor immunotherapy drug in combination with the ferroptosis sensitizer, the impact on tumor growth was considerably stronger than with one or more the other only agents. The researchers concluded that the badociation of a ferroptosis sensitizer and a checkpoint inhibitor creates a strong immune response that fights the tumor by causing a ferroptosis. In cancer patients treated with immunotherapy, the signs of ferroptosis correlated with the benefits of treatment.

"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 better understand this and develop different mechanisms."

This is the first step and Zou cites many questions that need to be explored and understood before the treatment progresses.

"Immunotherapy is only effective in about 30% of cancer patients.Our findings provide new insights to understand and explore how to make the immune system work for more patients," Zou said.