Abstract
Glioblastoma (GBM) is a highly aggressive and the most common primary malignant tumor of the central nervous system (CNS) in adults. Several obstacles to developing immunotherapies for GBM include an incomplete understanding of CNS-specific antigen presentation and T cell priming. Recent literature has suggested the dura as an important site for immune activation in preclinical models. However, the exact anatomic locations within the dura, especially in glioma-bearing mice, remain unclear. To better understand this process, we sought to characterize the immune cell composition and accumulation of tumor-associated materials within different regions of the dura. Specifically, we dissected the dura from tumor- or PBS-injected mice into anatomically distinct regions including the superior sagittal sinus (SSS), transverse sinus (TS), dural-associated lymphoid tissue (DALT), and non-sinus regions (NS). Through flow cytometry, we observed heterogeneity in immune cell infiltration into these different dural sites from glioma-bearing mice compared to that of PBS injected controls. Most importantly, CD3(+) T cells increased throughout the dura in response to tumor injection, with preferential infiltration into the DALT, SSS, and NS regions (>2 fold compared to PBS) compared to the TS region (~1.2 fold). CD8(+) and CD4(+) T cells, as well as cDC2 cells, followed similar infiltration trends. Conversely, cDC1 had the highest infiltration into the TS and NS regions (~28 fold) compared to the DALT and SSS regions (~15, ~20 fold, respectively). In addition, we employed a fluorescently labeled tumor cell line to track immune-mediated transportation of tumor materials. Through both flow cytometry and confocal imaging of the dura, we detected the presence of immune cells with tumor-derived fluorophore in various regions of the dura. Thus, these findings suggest that the dura, especially the DALT, is an important site of immune activation and leveraging this unique tissue site may offer new opportunities for GBM immunotherapy.