The role of stress-induced glucocorticoids in glioma development, progression and immunotherapy responsiveness

This project will assess how chronic stress, and the ensuing
production of glucocorticoid hormones, affect the development of
primary brain tumors and its response to immunotherapy, in particular
immune checkpoint therapy. Since immunity has emerged as a
critical player during tumor development, we will first reveal how
chronic stress affects the brain’s immune system in healthy mice.
This includes the evaluation of stress-induced effects on (1) the
composition, activation and distribution of all brain immune cells; (2)
the functioning of the brain's lymphatic system and (3) the ability of
the brain's border regions to attract and activate tumor-reactive
immune cells. As tissue macrophages and dendritic cells are the
brain's main orchestrators of an immune response, we will
specifically evaluate their role in glucocorticoid-sensing and stressinduced immune adaptation. Next, by employing a mouse model of
spontaneous glioma development, we will assess whether chronic
stress affects the development of gliomas and its tumor immune
compartment. Finally, we will investigate whether chronic stress may
impair the efficacy of brain tumor immunotherapy and whether this
may be alleviated via the co-administration of glucocorticoid receptor
(GR) inhibitors.