Carine Michiels

CDR - Macrophage reprograming by protontherapy

Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging and survival rates remain stagnant. Recent clinical trials have demonstrated promising results with immune checkpoint blockers but their success is mitigated by the immunosuppressive properties of the tumor microenvironment. Tumor-associated macrophages (TAMs) represent the most important immune cell compartment in tumor and more than 70% of them are M2-like macrophages with efficient immunosuppressive activities.

Therefore, retuning of TAM to M1 phenotype, competent for T cell activation, would be a key for effective immunotherapy. Radiotherapy based on X rays has been demonstrated to improve tumor immune rejection both by inducing immunogenic cell death but also by affecting myeloid cells. However, nothing is known regarding the effects of protontherapy.

 In this work, we will systematically compare both types of irradiation using appropriate in vitro cell cultures and in vivo murine tumor models to trigger TAM-to-M1 conversion and investigate its possible synergy with immunotherapy for tumor eradication. Preliminary results indeed showed that proton irradiation modified the phenotype of human M2 macrophages in vitro.

These results will be completed in vitro and in vivo and the combination with anti-PD-L1 treatment in vivo will be investigated. In addition to tumor size and survival, different parameters will be studied, notably the number and the phenotype of macrophages and T cells within the tumors, the abundance of immunosuppressive and immune-stimulating cytokines and the apoptosis of cancer cells. The results may guide precision medicine approaches by revealing tumor microenvironment components that influence treatment responses.