Blocking TET2 Could Help Radiation Treatments Fight Cancer

Radiation therapy can trigger an unwanted immune response

Radiation therapy is designed to damage tumor-cell DNA, and it remains a mainstay of cancer treatment. Yet its effects do not stop at the tumor. Researchers at the University of Chicago report that radiation can also reshape immune cells produced in the bone marrow, pushing some of them toward a state that protects tumors from immune attack.

The study, published in Cancer Cell, identifies the protein TET2 as a key part of that process. In the researchers’ experiments, blocking TET2 changed the behavior of radiation-activated immune cells, allowing them to support anti-cancer activity instead of suppressing it. The intervention also helped radiation and immunotherapy shrink tumors and control metastasis in the study’s models.

The finding does not establish a new treatment for patients. It does, however, offer a detailed explanation for one reason radiation and immunotherapy may not work equally well for every person—and points to a potential way to improve the combination.

The cells that can blunt an anti-tumor response

Between 50% and 60% of cancer patients receive radiation therapy, according to the University of Chicago summary of the work. While the treatment can kill cancer cells directly, it can also expand a population of immune cells called myeloid-derived suppressor cells, or MDSCs.

MDSCs arise in the bone marrow and can travel to tumors. Once there, they dampen the activity of CD8-positive T cells, which are among the immune system’s principal tumor-killing cells. A rise in MDSCs after radiation has been associated with shorter survival and a higher risk of metastasis in patients.

That creates a difficult therapeutic contradiction. Radiation can release signals from damaged cancer cells that might help the immune system recognize a tumor, but it can simultaneously foster an immune environment that limits the response. Understanding which molecular switch drives that second effect is therefore important for efforts to combine radiation with checkpoint-blocking immunotherapies.

TET2 emerged as a possible switch

The University of Chicago team examined blood samples collected before and after treatment from 33 people with stage IV non-small cell lung cancer. The patients had enrolled in a clinical trial combining high-dose, precisely targeted radiation with the immunotherapies nivolumab and ipilimumab.

Among the immune-cell types examined, MDSCs showed the highest levels of TET2. TET2 levels increased further after radiation, especially in patients whose cancers did not respond to treatment. The researchers also noted previous reports linking TET2 mutations in blood cells with better responses to immunotherapy, an observation consistent with the possibility that TET2 can hinder an effective anti-tumor immune response.

TET2 is an enzyme involved in removing methyl groups, chemical tags that can influence how genetic information is regulated. In this work, radiation activated TET2 in bone-marrow immune cells, where the protein removed chemical tags from RNA and helped lock the cells into an immune-suppressing state.

This mechanism matters because it shifts attention beyond the cancer cells receiving radiation. The response of distant bone-marrow-derived cells may shape whether treatment produces a more hostile or more permissive environment for a tumor.

Blocking the pathway redirected immune cells

When researchers blocked TET2, the immune cells that had been reprogrammed by radiation began acting against cancer rather than protecting it. In the reported experiments, the change strengthened the effects of radiation and immunotherapy, helping to reduce tumors and limit metastatic disease.

The result suggests that TET2 inhibition could eventually become a way to prevent radiation-induced immune suppression. Rather than treating radiation’s immune effects as a fixed tradeoff, clinicians may someday be able to manipulate the underlying pathway and preserve more of the treatment’s anti-tumor potential.

That prospect remains preliminary. The supplied report describes a mechanistic study and experimental results, not evidence that a TET2-targeting approach is ready for routine clinical use. Any future therapy would need to establish how to inhibit the pathway safely, when to administer an inhibitor relative to radiation and immunotherapy, and which patients are most likely to benefit.

Why the result could matter for combination treatment

Radiation and immunotherapy are increasingly studied together because each can influence the other. Radiation attacks a local tumor site, while immunotherapy seeks to restore or amplify immune responses that can reach cancer throughout the body. But the immune system contains both tumor-fighting and tumor-suppressing components. The new findings underline that successful combinations may depend on controlling both sides of that balance.

The patient-sample analysis is particularly notable because it connected the proposed pathway to treatment response in people with advanced lung cancer. Patients with the sharpest post-radiation increase in TET2 were among those whose cancers did not respond, giving the laboratory findings a clinical context.

The next challenge is translation. Researchers will need to determine whether TET2 levels can serve as a biomarker for radiation-associated immune suppression, whether the signal applies across cancer types, and whether intervening in the pathway improves outcomes without creating unacceptable immune complications.

A more precise view of radiation’s immune effects

For now, the study provides a more precise account of how a therapy intended to damage tumors can inadvertently aid them. It also offers a potential target for countering that effect. If further research validates the approach, TET2 could become part of a strategy to make radiation-immunotherapy combinations more consistently effective.

The central lesson is that radiation’s value may depend not only on the dose delivered to a tumor, but also on the immune programs activated elsewhere in the body. By identifying one of those programs, the University of Chicago researchers have opened a path toward testing whether it can be redirected in patients.

This article is based on reporting by Medical Xpress. Read the original article.