BACKGROUND: Glioblastoma, a universally fatal brain tumor, commonly presents in the elderly (median onset 65 years), yet preclinical studies are conducted in 6-8 week old mice; the equivalent of a teenager. Endogenous dendritic cells (DCs) carry antigen from the glioblastoma microenvironment to draining lymph nodes (LNs) via meningeal lymphatic vessels (MLVs) resulting in anti-tumor immunity. DC vaccines (DCV) in cancer have shown some success, however glioblastoma patients older than 60 receiving DCV have significantly worse survival compared to younger patients. We aim to determine how aging affects endogenous glioblastoma immunity, DCV, and outcomes.
METHODS: Mice aged 85-90 weeks were intracranially implanted with orthotopic glioblastoma tumor models. Endogenous antitumor immune responses and DCV phenotype and functionality were compared with young mice (6-8 week-old).
RESULTS: Aged mice have shorter survival with two glioblastoma models. Following fluorescent bead injection into tumor, bead+ DCs, neutrophils, and eosinophils accumulate in the meninges of aged mice. Correspondingly, there is a reduction in the expression of the LN homing activation receptor VEGFR3 within MLVs, suggesting impaired lymphatic drainage. Surprisingly, young and aged DCV were phenotypically similar in vitro (CD40, CD80, CD86, and PD-L1) and when pulsed with SIINFEKL peptide, aged DCVs efficiently activate OT-I T cells. Upon transfer into either young or aged hosts, recovered DCV maintain their similar phenotypes. However, aged mice have a decrease in naïve T cells, which could affect DCV functionality in vivo.
CONCLUSION: Effective MLV drainage is compromised in aged mice with glioblastoma, and this is associated with worse outcomes. While aged DCVs retain their phenotype and in vitro function, reduced naïve T cell availability in aged hosts may limit their effectiveness in vivo. Future studies will determine whether MLV drainage homing molecule expression and DCV-induced T cell activation are reduced in vivo, resulting in poorer survival outcomes.