MTOR SIGNALING IN GLIOMA-ASSOCIATED MICROGLIA AND MACROPHAGES

In patients with glioblastoma (GBM) overall survival is still dismal despite improved diagnostic precision and aggressive treatment strategies including recent trials that target selective cancer alterations or immune cell-based therapies. While the central nervous system (CNS) is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect GBM progression and treatment resistance. The impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), onto patients’ clinical course is still unclear, although different GAM subpopulations are positively associated with patients’ survival. Likewise, only limited data exists on the effect of established as well as novel targeted therapies on GAMs and the resulting potential impact on therapeutic responses. We analyzed GAM properties (proliferation, cell death, migration, cytokine expression) in a GBM co-culture in vitro model under standard chemotherapy with temozolomide and targeted therapy with mTOR inhibition. We identified the mTOR signaling cascade not only as a central regulator of glioma cells but also GAM function. MTOR inhibition regulated the proliferation and cytokine expression profile of GAMs with an increase of the inflammatory cytokines macrophage migration inhibitory factor (MIF) and plasminogen activator inhibitor-1 (PAI-1). These effects might influence the efficacy of mTOR inhibitor therapies in GBM patients. A more detailed understanding of therapy-mediated effects on GAMs will augment the design of effective treatment combinations and identification of patient subgroups most likely to benefit from therapeutic interventions with established and novel targeted therapies.