Cancer-fighting T cells need small amounts of ROS to attack tumors, study finds

New research reveals a promising new target for treating cancer by harnessing a type of molecule previously thought to do more harm than good. 

For decades, reactive oxygen species, or ROS, often called free radicals, have been viewed primarily as harmful molecules linked to aging, DNA damage and cancer. A new study co-led by Oregon Health & Science University finds that cancer-fighting T cells need small amounts of ROS to attack tumors. 

The investigators discovered that cancers exploit the T cell need for ROS by releasing an antioxidant protein that removes ROS from the tumor environment, effectively shutting down the attack by the immune system upon the cancer. 

Published today in the journal Science, the findings identify a previously unknown way tumors escape immune attack and point to a promising new target for cancer immunotherapy. 

The research was co-led by physician-scientist Robert L. Eil, M.D., associate professor of surgery in the OHSU School of Medicine and member of the OHSU Knight Cancer Institute, alongside investigators at the University of Cambridge. 

One of the surprising findings is that antioxidants aren't always beneficial in the context of cancer. While reactive oxygen species sound threatening, T cells actually need them to perform their tumor-fighting job. What we found is that tumors can exploit the T cell's dependency by removing the reactive oxygen species the immune system depends on." 

Robert L. Eil, M.D., associate professor of surgery, OHSU School of Medicine

By analyzing tumor interstitial fluid, the liquid that surrounds cells within tumors, researchers found that tumors create an antioxidant-rich environment that essentially chemically "smothers" T cells. The team identified high levels of an antioxidant enzyme known as peroxiredoxin-1, or PRDX1, which neutralizes the ROS within the tumor microenvironment, depriving the T cells of the signals they need to activate and attack cancer cells. 

"We tend to think of reactive oxygen species purely as damaging byproducts of metabolism. But we are increasingly understanding that ROS have important functions within cells, and T cells require them to activate," said Alexander J. Wesolowski, Ph.D., first author of the study and a researcher in the Department of Pathology at the University of Cambridge. "Our study develops this picture, revealing that tumors can exploit this very dependency to evade elimination." 

How tumors silence T cells 

The findings may also help explain a long-standing mystery in cancer research. 

To determine whether PRDX1 directly contributes to tumor immune evasion, researchers used CRISPR gene-editing technology to create cancer cells that could no longer produce antioxidant protein. 

Removing PRDX1 enhanced immune activity and reduced tumor growth in multiple experimental models. In one melanoma model, tumors lacking PRDX1 were spontaneously rejected by the immune system. In others, eliminating PRDX1 made previously resistant tumors responsive to immune checkpoint blockade, a form of immunotherapy that helps T cells recognize and attack cancer. 

The research team also investigated whether the same mechanism occurs in people. They analyzed published datasets from human cancer cell lines, examined gene activity across thousands of human tumors and measured PRDX1 in fluid collected from patient tumors. Across all three approaches, researchers found evidence that human cancers also release PRDX1 into their surroundings, where it can suppress T cell activity. 

The findings are especially significant because many cancers either do not respond to immunotherapy or eventually develop resistance. 

"The immune system has already shown us that it can eradicate advanced cancers in some patients," Eil said. "The challenge is that current immunotherapies don't work for most people, and even when they do, complete responses remain relatively uncommon. The more we understand how tumors suppress T cells, the more opportunities we have to design therapies that reverse that suppression." 

Researchers describe PRDX1 as part of a previously unrecognized "redox checkpoint," a mechanism by which tumors manipulate ROS levels to suppress anti-tumor immunity. The study found that cancer cells increase PRDX1 expression during a process known as immunoediting, in which tumors evolve under pressure from the immune system and acquire characteristics that help them escape immune attack. 

Considering future therapies 

Researchers are considering how they might be translated into future therapies. 

Potential approaches include drugs that neutralize tumor-derived antioxidants, therapies that block PRDX1 activity and engineered immune cells designed to resist the suppressive effects of antioxidant-rich tumor environments. 

"What's exciting is that we've identified a target nobody was really looking for before," Eil said. "This doesn't put a drug in patients' hands tomorrow, but it gives us an entirely new pathway to pursue. Discovering new targets is how future treatments begin." 

Eil said his team and collaborators will continue studying how tumors suppress immune responses and how those mechanisms can be overcome through next-generation immunotherapies, including engineered T cell therapies.

"This is one more victory against ignorance in understanding why cancers are so difficult to treat," Eil said. "Every time we uncover a new way tumors suppress the immune system, we gain another opportunity to fight back. That's how better treatments are built." 

 In addition to OHSU and the University of Cambridge, the study included researchers from the Babraham Institute in England, the University of Tübingen, Germany, the University of Lausanne, Switzerland, the Humanitas Clinical and Research Center, Italy, and other collaborating institutions.