Abscopal Effects of Local Radiotherapy Are Dependent on Tumor Immunogenicity

Abstract

Although abscopal tumor regression remains a rare phenomenon, interest in exploiting how radiation stimulates the immune system to induce systemic abscopal response is increasing. Here, we tested the hypothesis that tumor immunogenicity determined the ability of radiotherapy to induce abscopal effects. We established highly (MC-38 and E.G7-OVA) or poorly (LL/2 and B16-F10) immunogenic tumor models in this study and treated them with sham radiation, a single dose of 15 Gy, or three fractions of 5 Gy on three consecutive days. Alterations in the tumor microenvironment after radiation were examined by flow cytometry and RNA sequencing. Our results demonstrated the positive correlation between tumor immunogenicity and the abscopal effect of radiotherapy. The single dose of 15 Gy radiation was an effective regimen for inducing abscopal effects in highly immunogenic tumors. Local radiation reshaped the tumor microenvironment of irradiated and non-irradiated distant tumors by increasing CD8 T-cell infiltration and reducing suppressive immune cell accumulation. However, radiation alone was insufficient to elicit abscopal effects in poorly immunogenic tumors. No significant alterations were detected in the non-irradiated distant tumor microenvironment after radiation of poorly immunogenic tumors. In addition, tumor immunogenic subtypes were associated with the radiological response and clinical outcome of patients receiving radiotherapy. These findings indicated that tumor immunogenicity was the dominant characteristic that could predict the abscopal effect of radiotherapy. Our study provides an in-depth understanding of the immunological mechanisms involved in abscopal effects and highlights the impact of tumor heterogeneity on the therapeutic efficacy of radiotherapy and their combination with immunotherapy in clinical trials.

Advances in immunotherapy for cervical cancer: recent developments and future directions

“…For example, anti-CD40 treatment and single-fraction radiation significantly improved tumor control and survival in a mouse model of cervical cancer 48. Radiation also changes the tumor microenvironment, even in non-irradiated distant tumors 49. However, the abscopal effect is controversial and is a rare phenomenon, with clinical data largely limited to case reports 50 51.…”

“…48 Radiation also changes the tumor microenvironment, even in non-irradiated distant tumors. 49 However, the abscopal effect is controversial and is a rare phenomenon, with clinical data largely limited to case reports. 50 51 Further research is ongoing to understand the treatments and patients for whom this is most likely to occur (eg, NCT03614949).…”

Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review

“…Surprising out-of-RT field responses were first reported in 1953 by Mole, raising the term of the abscopal effect (from the Latin ab scopus: far from the target) [ 163 ]. This phenomenom was defined as the regression of out-of-field metastatic lesions after local radiotherapy [ 164 ]. The immuno-modulation of stereotactic radiotherapy could be explained by the complex cascade of biological responses following its delivery, including DNA damage directly on the tumor cells, as well as on the tumor-associated strama and endothelium, with the initiation and circulation of various signal transduction pathways leading to a proinflammatory tumor microenvironnement (TME).…”

Narrative Review of Synergistics Effects of Combining Immunotherapy and Stereotactic Radiation Therapy

“…To this day, this phenomenon remains rare [ 18 ]. It is defined as the further regression of other secondary tumor lesions in out of field sites after local radiotherapy, analogous to a distant bystander effect [ 19 ]. Current major advances in immunotherapy have led many studies to reconsider this potential effect of radiotherapy, especially through hypofractionated ablative irradiation.…”