Radiation Activates Protein TET2 in Bone Marrow
University of Chicago researchers have identified a biological mechanism that causes immune cells reprogrammed by radiation therapy to shield tumors instead of attacking them. Radiation activates a protein named TET2 on immune cells located in the bone marrow. This enzyme strips chemical tags from RNA, locking those cells into an immunosuppressive state.
Radiation therapy kills cancer cells by damaging their DNA, but it also prompts the expansion of myeloid-derived suppressor cells, or MDSCs. These bone-marrow-derived cells travel to tumors and block CD8⁺ T cells, which serve as the immune system’s primary tumor-killing agents. Data from a clinical trial at UChicago Medicine involving 33 patients with stage IV non-small cell lung cancer showed that rising MDSC levels following radiation correlate with shorter survival rates and higher risks of metastasis.
Protein Deletion Restores Antitumor Immunity in Mice
To evaluate the role of TET2, the research team studied mouse models with genetic deletions of TET2 specifically in myeloid cells. In tests involving colon cancer, melanoma, and lung cancer models, these modified mice exhibited slower tumor growth, extended survival, and fewer, smaller lung metastases after receiving radiation compared to normal mice. The study was published in Cancer Cell.
Cellular damage triggers the p53 protein within a day of radiation exposure, which subsequently activates TET2 in the bone marrow before the affected cells migrate to the tumor site. TET2 removes 5-methylcytosine marks from chromatin-associated RNAs inside the nucleus. This loss compacts the chromatin and silences genes responsible for producing type I interferon, a signaling molecule that alerts the immune system to threats.
Experimental Drugs Target TET2 to Enhance Immunotherapy
When researchers blocked TET2 using an experimental drug, treated subjects showed reduced tumor growth and fewer lung metastases when the therapy was combined with radiation. This intervention transformed immunosuppressive myeloid cells into myeloid-derived activating cells, or MDACs. Unlike MDSCs, MDACs present tumor protein fragments to CD8⁺ T cells, priming them to mount an immune attack against the cancer.
Blocking TET2 changes these immunosuppressive myeloid cells into an immunostimulant, antigen-presenting myeloid compartment that enhances immunotherapy and radiotherapy responses while markedly decreasing distant metastasis, according to senior author Ralph Weichselbaum. The research team is currently investigating how to test TET2 inhibitors alongside radiation therapy in patients.
Frequently Asked Questions About TET2 and Radiation
What percentage of cancer patients receive radiation therapy?
Radiation therapy is administered to 50% to 60% of cancer patients to kill tumor cells by damaging their DNA.
How does TET2 affect RNA in immune cells?
TET2 removes 5-methylcytosine chemical tags from chromatin-associated RNAs, which compacts the chromatin and silences the interferon signaling pathway that alerts the immune system.
What type of patients provided blood samples for the UChicago study?
The study analyzed blood samples from 33 patients with stage IV non-small cell lung cancer enrolled in a clinical trial that combined high-dose targeted radiation with nivolumab and ipilimumab.
What is the difference between MDSCs and MDACs?
MDSCs dampen the immune response and block tumor-killing T cells, whereas MDACs present tumor proteins to CD8⁺ T cells and prime them to attack cancer.
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