Radiation therapy boosts immunosuppressive cells … a “fate switch” blocks cancer resistance and metastasis

A clue has emerged that could help overcome a limitation of radiation therapy: It can boost immunosuppressive cells, leading to cancer resistance and metastasis.

A research team led by He Chuan, Ralph Weichselbaum and Hua Laura Liang at the University of Chicago reported on the 17th (local time) in the international journal Cancer Cell that it had identified a “switch” that changes the fate of myeloid cells after radiation therapy.

Radiation therapy is a standard treatment used in 50~60% of patients with cancer, but while killing tumors, it also increases immunosuppressive myeloid-derived suppressor cells (MDSCs), leading to treatment resistance and metastasis.

The team found that radiation activates an enzyme called TET2 in myeloid cells, which oxidizes 5-methylcytosine (m5C) in chromatin-associated RNA (caRNA), and that this process forces differentiation into immunosuppressive MDSCs.

Conversely, removing TET2 allowed the MBD6-BAP1 complex to erase this mark, shifting differentiation toward immunostimulatory “myeloid-derived activating cells (MDACs).”

The resulting MDACs were found to restore interferon signaling, enhance the antitumor immunity of radiation therapy and suppress metastasis.

The researchers said, “We showed for the first time that m5C in caRNA directly regulates chromatin state and the fate of myeloid cells,” adding that “reprogramming myeloid cells could be a strategy to overcome treatment resistance and metastasis.”