Immunotherapy in CNS cancers: the role of immune cell trafficking

Abstract

Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden. One of the major setbacks in translating immunotherapy strategies is the hostile microenvironment of the tumor that inhibits trafficking of effector immune cells such as cytotoxic T lymphocytes into the CNS. Incorporating important findings from autoimmune disorders such as multiple sclerosis to understand and thereby enhance cytotoxic lymphocyte infiltration into GBM could augment immunotherapy strategies to treat this disease. However, although these therapies are designed to evoke a potent immune response, limited space in the brain and cranial vault reduces tolerance for immune therapy-induced inflammation and resultant brain edema. Therefore, successful immunotherapy requires that a delicate balance be maintained between activating and retaining lasting antitumor immunity.

Fig. 1

Routes for leukocyte trafficking in the CNS. Three main routes have been described for leukocyte trafficking from the blood vasculature to the brain. A parallel lymphatic system allows for drainage of CSF (carrying cells and tumor antigens) and interstitial fluid (carrying tumor antigens, but not cells, along arteries, retrograde to blood flow) to the cervical lymph node. T cells engage antigen:MHC complexes presented by peripheral APCs in the lymph node, and activated lymphocytes can thereby enter the brain through the routes thus described. (a) The subarachnoid space (SAS) through leptomeningeal vessels. The leptomeninges are formed by the arachnoid mater, the pia mater, and the CSF in the SAS. Lymphocytes and APCs in the SAS present antigen and may engage T cells. (b) The perivascular space through postcapillary venules. Endothelial cells in postcapillary venules within the parenchyma are joined by tight junctions. T cells that traverse this layer enter the perivascular space within the brain parenchyma. (c) The CSF through the choroid plexus. Blood leukocytes cross the fenestrated endothelial layer to enter the choroid plexus stroma. The choroid plexus epithelial basement membrane and tight junctions between epithelial cells form the BCSFB. T cells that cross the BCSFB enter the CSF within the ventricles.