Photodynamic Opening of the Blood-Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors

Abstract

Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood-brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.

Keywords: blood-brain barrier; glioblastoma; immunotherapy for brain tumors; meningeal lymphatic vessels; photodynamic therapy.

Figure 1

Schematic illustration of intracavitary PDT and interstitial PDT for GBM with an energy diagram of the oxygen response after PS excitation by an appropriate light wavelength. In the singlet state, energy is converted to heat by internal conversion or emitted as fluorescence. Then, PS in the excited singlet state can convert to the excited triplet state. In the triplet state, the energy can undergo a Type 1 or Type 2 redox reaction with the generation of the reactive oxygen species (ROS), which induces the death of the GBM cells via necrosis and/or apoptosis. This can also destruct the GBM vasculature and produce an acute inflammatory response that attracts leukocyte activation.

Figure 2

The lymphatic clearance of tracer from the brain after crossing the OBBB. The figure illustrates the fluorescent microscopy of the clearance of TRITC-dextran 70 kDa (red color) from the brain via the meningeal lymphatics (green color, labelled by the specific antibodies LYVE-1 conjugated with Alexa 488). The intravenously injected TRITC-dextran is immediately observed in the Sagittal sinus (the main cerebral vein), and 30 min later, it is also present in the meningeal lymphatics due to the PDT-OBBB-mediated activation of the lymphatic clearance of tracer from the brain [43].

Figure 3

Schematic illustration of the depth of the penetration of light into the head and brain tissues, depending on the wavelength.

Figure 4

PDT-OBBB modulation of brain tumor immunity. The cancer immunity cycle in GBM involves the APC release and lymphatic traffic of APCs into the dCLNs (1), where they activate CD4+/CD8+-T cells (2). The T-cells migrate from the dcLNs to the GBM, extravasate into the tumor tissues via OBBB (3), and, finally, the T cells induce GBM cytotoxicity, releasing more GBM antigens and contributing to brain tumor immunity.