Proton irradiation-induced tumor macrophage rewiring in order to boost immunotherapy

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 immunostimulating
cytokines and the apoptosis of cancer cells. The results may guide precision
medicine approaches by revealing tumor microenvironment components
that influence treatment responses.