The Spatiotemporal Evolution of Radiation Resistance in Glioblastoma.

BACKGROUND

Although radiation therapy (RT) remains one of the most effective treatments for patients with the lethal brain tumor glioblastoma (GBM), quite a number of patients show resistance or relapse shortly after RT. There is an urgent need to uncover the temporal and spatial dynamics of RT resistance during tumor progression and treatment.

METHODS

The radio-resistance signature score (RRSS) was calculated by utilizing glioma sphere-forming cells (GSCs) which recapitulate the transcriptomic landscape of GBM.

RESULTS

RRSS can assess the RT response on both cell lines and GBM patients. Both transdifferentiated and irradiated glioma cells show increased radiation resistance, demonstrating that the recurrent GBM may acquire resistance along with cell differentiation and selective advantage during treatment. Moreover, RRSS of the marginal tumors is found to be higher than that of core tumors (Wilcoxon's rank-sum test, p-value<0.01). The infiltration of macrophages was significantly associated with radiation resistance (p-value<0.01), which was further validated by single-cell RNAseq based experiments and clonogenic assays. Moreover, we demonstrated that IL1B, a pro-inflammatory cytokine secreted by macrophages, could enhance the radiation resistance of tumor cells.

CONCLUSIONS

Our study revealed the spatiotemporal evolution of radiation resistance of GBM, and shed light on the development of novel adjuvant therapeutic strategies.