Radiotherapy enhances M1 macrophage immunogenic activity through IFNs induction and stimulation in TP53-wild type tumors.

Radiotherapy (RT), widely employed in clinical practice to suppress tumor progression, exhibits an abscopal effect that enhances immunogenic activity to potentially benefit immunotherapeutic efficacy. However, the tumor types most likely to exhibit such effects remain unclear. Since TP53-wild type tumors are sensitive to RT, we hypothesized and aimed to investigate whether these tumors are prone to RT-induced abscopal effects. Bioinformatic analyses with RNAseq were conducted to identify the differentially expressed genes. Next, quantitative polymerase chain reaction with flow cytometry was used to assess the potential mechanism. In liver hepatocellular carcinoma (LIHC), a cancer type with a 27% TP53 mutation (therefore 73% TP53-wild type), we noticed that p53 expression positively correlated with the 15 selective immunotherapy-associated genes. We consequently validated that the IFNγ-up-regulated genes in TP53-wild type A549 cells were correlated with better immunotherapeutic outcomes. In contrast, RT induced a distinct set of genes enriched in p53 signaling pathways to correlate with better survival in LIHC patients, but not with immunotherapeutic response. Even so, we found that RT specifically induced apoptosis in TP53-wild type HCT116 cells compared to TP53null HCT116 cells to significantly promote immune cell activation in vitro. We consequently demonstrated the major factors, including IFNα and IFNγ expression, induced by RT in TP53-wild type tumors potentially enhance M1 macrophage polarization, whereas these effects were absent in TP53null models. In conclusion, our findings demonstrate that RT specifically suppressed TP53-wild type tumors, leading to IFNs expression. The RT-mediated immunogenic activation was potentially derived from the RT-induced IFNs, which were speculated to contribute to M1 macrophage polarization and immunogenic activity. These results suggest TP53-wild type tumors may be ideal candidates for combining RT and immunotherapy in clinical settings.