On the Immunological Consequences of Conventionally Fractionated Radiotherapy: In silico Insights

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Emerging evidence demonstrates that radiotherapy induces immunogenic cell death on tumor cells that emits immunostimulating signals, resulting in tumor-specific local and systemic immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we propose a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Model simulations suggest that radiotherapy success depends on the extent of functional tumor vascularity, which in turn influences the efficacy of radiation-induced immune responses. Simulation analysis revealed that tumor size at time of treatment is not a consistent determinant of radiotherapy outcomes. While small radioresistant tumors could not be eradicated by radiotherapy due to an insufficient radiation-induced antitumor immunity, poor treatment outcomes of large tumors could be attributable to an insufficient burden reduction by radiotherapy. Notably, tumors of intermediate size were more responsive due to an adequate balance between radiotherapy-induced immunostimulation and tumor shrinkage. The one-size-fits-all approach of conventionally fractionated radiotherapy was predicted to result in some overtreated patients receiving doses in excess. Model analysis also suggest that an arbitrary increase in treatment duration does not necessarily imply enhanced tumor control, because radiation-induced antitumor immunity could be mitigated after a certain number of treatment fractions. Depending on tumor features, weekend breaks during conventional radiotherapy could induce robust tumor-specific immune responses outperforming fractionation schemes daily delivered without weekend interruptions. Modeling findings highlight the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential radiotherapy and enhance tumor control.