Connection Between Tumor Radiosensitivity and Response to Immunotherapy in 11 Major Epithelial Cancer Types

Background: Radiotherapy has gained increasing attention as an effective cytotoxic agent to improve therapeutic response to immunotherapy. However, synergic effect is seldom seen clinically and reliable biomarkers for optimal patient selection remains to be identified. Radiosensitivity index (RSI) is a well-known measure of tumor’s response to radiotherapy, which is derived from genomic data and system biology. Its association with the immune landscape in cancer is unclear. Methods: Genomic data from Merged Microarray-Acquired dataset (MMD) were established and the Cancer Genome Atlas (TCGA) were obtained. Based on rank-based regression model including 10 genes, RSI was calculated. A total of 12,832 primary tumors across 11 major cancer types were analyzed. RSI was stratified into RSI-Low and RSI-High by a cutpoint of 0.46. Gene set variance analysis was applied to measure the genomic pathway activity (18 genes for T-cell inflamed activity). Kaplan-Meier analysis was performed for survival analysis. Findings: We found that RSI was significantly associated with homologous DNA repair, cancer stemness and various cancer-specific molecular features. Tumors with low RSI were associated with significantly higher portion of M1 macrophage, relative to M2 macrophage, and higher IFNG expression. Additionally, dominant interferon-γ (IFN-γ) response was characterized by low RSI and potentially predicted better response to programmed cell death 1 (PD-1) blockade. Interpretation: RSI is strongly associated with immune response and efficacy to PD-1 blockade. IFN-γ dominant status could be estimated by RSI, providing an alternative selection strategy to identify suitable patients for combined radiotherapy and immunotherapy. Funding Statement: This study was supported by study project of Tri-Service General Hospital (TSGH-D109063). Declaration of Interests: The authors declare that they have no competing interests.