Macrophages play a central role in tissue homeostasis, orchestration and resolution of inflammation, and tissue repair but they also support tumor growth and are suspected to promote resistance to radioimmunotherapy. These pleiotropic actions are based on the pronounced plasticity of the macrophage phenotype that differs depending on tissue/tumor type, microenvironment and treatment. We revealed that radiation-induced environmental changes in normal and tumor tissues induce monocyte/macrophage recruitment, (re)polarization and phenotypic changes towards M2-like pro-fibrotic or pro-tumorigenic phenotypes. However therapy-induced phenotypic changes, as well as phenotypic similarities and differences between TAMs and fibrosis-associated macrophages, require further definition if we aim to target macrophage responses to improve treatment outcome. Here we aim to define the role of macrophage plasticity (TME-induced, therapy-induced) for both, the efficacy and toxicity of radiotherapy and combined radio-immunotherapy.
Using adequate in vitro co-culture systems and in vivo tumor and normal tissue toxicity models in immunocompetent mice this project will establish spatiotemporal local and systemic changes in the macrophage molecular repertoire during the course of radiation treatment (blood, tumor, normal tissue), their impact on other immune cell types, and potential radiation-induced environmental changes driving phenotypic immune changes in tumor and normal tissues. This research will reveal response-markers and therapeutic targets for improving efficacy of radio(immuno)therapy without increasing toxicity by targeting macrophage-induced therapy escape.