The Effects of Radiation Dose Heterogeneity on the Tumor Microenvironment and Anti-Tumor Immunity

Radiotherapy elicits dose- and lineage-dependent effects on immune cell survival, migration, activation, and proliferation in targeted tumor microenvironments. Radiation also stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has raised interest in using radiotherapy to promote greater response to immunotherapies. To clarify the potential of such combinations, it is critical to understand how best to administer radiation therapy to achieve activation of desired immunologic mechanisms. In considering the multifaceted process of priming and propagating anti-tumor immune response, radiation dose heterogeneity emerges as a potential means for simultaneously engaging diverse dose-dependent effects in a single tumor environment. Recent work in spatially fractionated external beam radiation therapy demonstrates the expansive immune responses achievable when a range of high to low dose radiation is delivered in a tumor. Brachytherapy and radiopharmaceutical therapies deliver inherently heterogeneous distributions of radiation that may contribute to immunogenicity. This review evaluates the interplay of radiation dose and anti-tumor immune response and explores emerging methodological approaches for investigating the effects of heterogeneous dose distribution on immune responses.