Tumor antioxidants suppress T cells by removing ROS

Tumor antioxidants suppress T cells in a way that turns a familiar biological idea on its head. Molecules normally associated with protection from oxidative damage can also deprive immune cells of chemical signals they need to mount an effective attack on cancer.

Alexander J. Wesolowski and colleagues traced this effect to the antioxidant enzyme peroxiredoxin 1, or PRDX1, which tumor cells can release into the space surrounding them.

Reactive oxygen species are usually discussed as harmful products of metabolism. At high levels, they can damage DNA, proteins and membranes. But biology also uses small, controlled amounts of these reactive molecules as signals. For T cells, that signaling role turns out to be particularly important.

When T cells need oxidants

Activation of a T cell involves a biochemical cascade rather than a single molecular switch. After the T-cell receptor recognizes its target, multiple enzymes relay the signal through the cell.

Some of those enzymes accelerate signaling, while phosphatases act as brakes by removing phosphate groups from signaling proteins. Reactive oxygen species can transiently oxidize and inhibit certain phosphatases. That temporary loss of braking activity allows receptor-driven kinase signaling to proceed, helping the T cell activate, proliferate and perform its effector functions.

The researchers found that the interstitial fluid surrounding cells inside tumors had unusually strong antioxidant activity. One of the proteins particularly enriched in this environment was PRDX1.

PRDX1 removes reactive oxygen species such as hydrogen peroxide. When extracellular PRDX1 lowers the concentration of these molecules around a T cell, the phosphatases are less likely to be oxidatively inhibited. They therefore continue suppressing the signaling cascade downstream of the T-cell receptor.

The result is a weaker activation signal and poorer T-cell function.

In effect, the tumor does not have to disable the immune cell directly. It can alter the chemistry of its surroundings and remove part of the signaling system the T cell depends on.

What happened when PRDX1 was removed

To test whether PRDX1 was actually contributing to immune escape, the researchers used CRISPR/Cas9 to generate cancer cells unable to produce normal amounts of the protein.

Loss of tumor-derived PRDX1 increased immune activity and restricted tumor growth across several mouse models. In one melanoma model, PRDX1-deficient tumors could be rejected by the immune system.

The effect was also relevant to immunotherapy. Some mouse tumors that had been resistant to immune checkpoint blockade became more responsive after PRDX1 was removed. Responses to antibodies targeting PD-1 and CTLA-4 improved in melanoma models, and combining PRDX1 loss with checkpoint therapy produced stronger tumor control in a mouse model of liver cancer.

The authors also found that Prdx1 expression increased during cancer immunoediting — the evolutionary process in which immune pressure selects tumor cells better able to survive immune attack. That observation is consistent with the idea that generating an antioxidant microenvironment can provide a selective advantage to tumor cells facing T-cell pressure.

Evidence from human cancers

The strongest causal experiments in the study were performed in cells and mice, but the team also asked whether the same pathway was present in human cancers.

In analyses of proteins secreted by 23 human cancer cell lines representing 11 cancer types, PRDX1 was prominent among extracellular antioxidant proteins. The researchers also examined gene-expression data from large collections of human tumors and analyzed interstitial fluid obtained from patient tumor tissue.

Together, those observations support the presence of extracellular PRDX1 in human tumors and make the mouse mechanism biologically plausible in people.

They do not show, however, that blocking PRDX1 will improve cancer treatment in patients. No PRDX1-targeting therapy was tested in humans, and the study does not establish the safety of deliberately increasing reactive oxygen species inside tumors.

That distinction matters because reactive oxygen species have two faces. Controlled amounts participate in normal signaling, but excessive levels can damage DNA and proteins and may also support processes involved in cancer progression. Any therapeutic attempt to manipulate this system would therefore need to change the redox environment selectively rather than simply increase oxidation throughout the body.

The study also does not establish that cancer patients should change their intake of dietary antioxidants or supplements. It investigates a specific molecular mechanism within the tumor microenvironment, not dietary intervention.

The broader lesson is that the chemistry surrounding an immune cell can be as important as the receptors on its surface. Here, a molecule normally associated with protection from oxidative stress becomes part of a tumor's immune-evasion strategy — while reactive oxygen species, usually cast as cellular villains, turn out to be necessary components of an effective T-cell signal.