Switching Off TET2 Turns Radiation-Triggered Immune Cells Against Tumours
University of Chicago researchers discover an RNA mechanism that converts cancer-protecting myeloid cells into active immune fighters.
By Giovanni Sapere
3 min readHuman-Edited, AI-Assisted
Radiation therapy kills cancer cells by damaging their DNA, yet it can also trigger the bone marrow to produce suppressor cells that protect surviving tumours. A research team at the University of Chicago has discovered that inhibiting an enzyme called TET2 reverses this effect, providing an epigenetic innovation that helps radiation and immunotherapy shrink lesions and curb metastasis. Their study, published in Cancer Cell, demonstrates the mechanism in clinical samples and animal models.
Radiation triggers suppressor cells in bone marrow
Between 50% and 60% of cancer patients undergo radiation therapy during treatment, according to findings reported by MedicalXpress. While the treatment damages malignant DNA, it frequently drives the expansion of myeloid-derived suppressor cells, known as MDSCs. These cells originate in bone marrow, travel to tumour sites, and inhibit tumour-killing CD8⁺ T cells, an outcome linked to reduced patient survival and higher rates of metastasis.
To understand this resistance mechanism, investigators analysed blood samples collected before and after treatment from 33 patients with stage IV non-small cell lung cancer enrolled in a clinical trial at UChicago Medicine, as detailed by MedicalXpress. The trial evaluated targeted high-dose radiation combined with two immunotherapy drugs, nivolumab and ipilimumab. Among all circulating immune cells, MDSCs displayed the highest concentrations of TET2, an enzyme known for detaching methyl groups from genetic structures. TET2 counts rose sharply after irradiation, specifically in patients whose disease failed to respond.
“If you block TET2, you change these immunosuppressive myeloid cells into an immunostimulant, antigen-presenting myeloid compartment that enhances immunotherapy and radiotherapy responses in mice and markedly decreases distant metastasis.”
— Ralph Weichselbaum, chair of radiation and cellular oncology at UChicago
An epigenetic switch on chromatin-associated RNA
Experiments revealed that radiation activates p53, a cellular damage sensor that switches on TET2 inside bone marrow within 24 hours of exposure, well before altered cells migrate into tumours, as reported by MedicalXpress. While TET2 has been widely studied for altering DNA, co-senior author Chuan He, professor of chemistry, biochemistry and molecular biology at UChicago and investigator at the Howard Hughes Medical Institute, showed that the enzyme also modifies RNA.
In irradiated cells, TET2 strips a chemical tag called 5-methylcytosine from chromatin-associated RNAs, causing nuclear chromatin to condense, as outlined by MedicalXpress. This compacting silences the genes responsible for producing type I interferon, an essential signalling molecule that alerts the immune system to malignant growth. When the team prevented TET2 from removing those chemical tags, a protein called MBD6 bound to the RNA, keeping chromatin accessible and sustaining active interferon pathways.
Drug inhibitors convert suppressor cells into tumour fighters
Unlocking that pathway reprogrammed the cells into a distinct biological class named myeloid-derived activating cells, or MDACs, according to MedicalXpress. Unlike suppressive cells, MDACs display tumour antigens directly to CD8⁺ T cells, directing them to attack malignant tissue. When transferred into mice with tumours, these activating cells restricted tumour expansion, matching clinical correlations where an MDAC genetic signature aligned with longer patient survival across multiple cancer types.
Because genetic deletion is not feasible in clinical practice, the researchers administered an experimental drug that blocks TET2, as noted by MedicalXpress. In mouse models of melanoma, colon cancer and lung cancer, combining the drug with radiation reduced the size and quantity of lung metastases while improving response to immunotherapy. Co-senior author Ralph Weichselbaum, chair of radiation and cellular oncology at UChicago, explained that the discovery provides a method to change suppressive myeloid cells into an immunostimulant compartment. The research team is now studying how TET2 inhibitors and chromatin-associated RNA targets could secure patent protection as the medical innovation moves through technology transfer pipelines toward human clinical trials.
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