A neuro-immune interface in glioblastoma

The treatment of glioblastoma needs groundbreaking advancements. Even with considerable progress in state-of-the-art techniques for most sophisticated molecular characterization of tumor tissue, the standard of care (SOC) in newly diagnosed disease has remained largely unchanged for decades. In this work, we report the discovery of hematopoietic stem and progenitor cells (HSPCs) present in the brain parenchyma of patients with glioblastoma. Their accumulation within the tumor tissue correlated with worse clinical outcomes, and in in-vitro models of disease, we determined that physical contact of HSPCs with tumor cells facilitated the increase of tumor-promoting features. The unexpected presence of cellular progeny of the hematopoietic system in the brain tumor then instructed an investigation of their potential roots of origin at the central nervous system (CNS) borders. Specifically, recent research has exposed guardian immune cells residing in the meninges, as well as around the dural venous sinus, and within the skull bone. As evident from preclinical models, these immune cells form a widespread yet local neuro-immune interface that responds to signals from the brain in conditions of injury or inflammation. This interface is connected via osseous liquor channels to the overlying cranial bone (CB), which acts as a locoregional source for immune cells of the meningeal sheets of the brain. The role of this structure in patients with glioblastoma, however, remains unknown. While searching for HSPCs, we discovered an unexpected niche of tumor-reactive, cytotoxic CD8+ T lymphocytes in the CB. These immune cells are capable to recognize and to respond in an anti-tumoral manner to the tumor cells from the glioblastoma parenchyma. It is remarkable that current SOC procedures in patients with brain tumors involve, as a first step of diagnosis and treatment, the disconnection of the CB. Our data suggest that this standard procedure may potentially harm the antitumor immune cell force. In light of these findings, future neoadjuvant settings of immunotherapies should be more focused on allowing the stimulation of potent cytotoxic immune responses before initiation of invasive treatment options.