Radiotherapy kills cancer cells both directly and through the instigation of anti-tumor immune responses, though tumors tend to develop resistance to the latter. Researchers led by Ludwig Chicago’s Liangliang Wang, Hua Laura Liang and Director Ralph Weichselbaum reported in a December paper in the Journal of Clinical Investigation a previously unknown mechanism by which such immune evasion occurs. It involves immunosuppressive myeloid-derived suppressor cells (MDSCs), which are immune cells that infiltrate tumors. The researchers found that in both mice and humans, ionizing radiation specifically dampens in MDSCs the expression of a protein named BAMBI. This protein is known to interfere with signaling by another protein, TGF-ß, which drives tumor progression. The researchers discovered that the m6A RNA-binding protein YTHDF2, which is also activated in MDSCs by ionizing radiation, directly binds and degrades transcripts of the BAMBI gene to silence its expression. Overexpressing BAMBI in MDSCs compromised their infiltration of tumors and suppression of immune responses. High expression of the protein in patients is associated with longer overall survival times for four types of cancer. Further, delivering BAMBI to the tumor microenvironment boosts the effects of radiotherapy and radioimmunotherapy in mouse models of cancer. The researchers suggest their findings support targeting BAMBI for cancer therapy.
Epitranscriptional regulation of TGF-β pseudoreceptor BAMBI by m6 A/YTHDF2 drives extrinsic radioresistance
Journal of Clinical Investigation, 2023 December 15