Programmed death ligand-1 (PD-L1) expression in various cancers including head and neck cancer favors cancer cell survival and proliferation as it allows them to escape the immune system. PD-L1 binds to its receptor at the surface of cytotoxic tumor infiltrating T cells (CD8+ TILs). and induces an inhibitory signaling pathway that interferes with T cell activation after specific antigen recognition through the T cell receptor. Blocking this negative pathway by preventing ligand-receptor interactions with an antibody is a Nobel Prize-winning powerful emerging tool in immunotherapy and frequently associated to conventional treatment strategies. Beyond PD-L1 expression, cancer cells are also capable of polarizing tumor-associated macrophages (TAMs) towards a M2-like phenotype, which adds several immunosuppressive properties to the tumor microenvironment and induces inactivation or even apoptosis of tumor infiltrating lymphocytes. It has been shown that radiotherapy can be used to repolarize macrophages from a M2 towards a M1-like immuno-stimulating phenotype. Furthermore, X- ray irradiation induces an increased PD-L1 expression in cancer cells through the activation of DNA-damage response pathways. Therefore, a treatment combining irradiation and an anti- PD-1 immune checkpoint blockage (ICB) effectively provoke cancer cell eradication by alleviating multiple immunosuppressive mechanisms present in numerous types of cancer, for instance in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the expression of PD-L1 after X-ray and proton irradiation at several doses and timings after irradiation, in order to determine in which condition an anti-PD-1 ICB in combination with X- ray irradiation would lead to an optimal treatment response. Based on these in vitro results, a syngenic in vivo mouse model of HNSCC was set up to assess TAM repolarization and its impact on CD8+ TIL activation and exhaustion. We discovered that unlike proton irradiation, X-ray irradiation induced a dose- and time dependent increase in PD-L1 expression, both at mRNA and protein levels. Additionally, although the combination of an anti-PD-1 ICB with X-ray irradiation increased tumor infiltration by immune cells and favors CD8+ TILs response to cancer cells, this process seemed not to be mediated by radiation-induced macrophage repolarization.
|Date of Award||17 Jan 2019|
|Supervisor||Carine MICHIELS (Supervisor)|