Immunotherapy for cancer in the central nervous system: Current and future directions

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and still remains incurable. Although immunotherapeutic vaccination against GBM has demonstrated immune-stimulating activity with some promising survival benefits, tumor relapse is common, highlighting the need for additional and/or combinatorial approaches. Recently, antibodies targeting immune checkpoints were demonstrated to generate impressive clinical responses against advanced melanoma and other malignancies, in addition to showing potential for enhancing vaccination and radiotherapy (RT). Here, we summarize the current knowledge of central nervous system (CNS) immunosuppression, evaluate past and current immunotherapeutic trials and discuss promising future immunotherapeutic directions to treat CNS-localized malignancies.

Keywords: Brain metastases; IDO; T cell therapy; glioblastoma; glioma; vaccination.

Figure 1.

Mechanisms and immunotherapeutic targets for glioblastoma (GBM). GBM cells, tumor-resident dendritic cells (DC) and myeloid-derived suppressor cells (MDSC) express indoleamine 2,3 dioxygenase 1 (IDO1). IDO1 expression is regulated by the Jak/STAT and NF-κB pathways, which is induced by IFNγ- and TGF-β-receptor activation, respectively. IDO1 is a cytoplasmic enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn). Within the GBM cell, Kyn complexes with the aryl hydrocarbon receptor (Ahr), cytoplasmically, facilitating the nuclear translocation and further docking with aryl hydrocarbon receptor nuclear translocator (ARNT) to transcriptionally regulate IL-6, acting as an autocrine loop that amplifies and sustains IDO1 expression. Simultaneously, extracellular Kyn suppresses T effector responses while activating regulatory T cell (Treg; CD4⁺CD25⁺FoxP3⁺) function through a presumably overlapping mechanism. IDO1 directly activates NF-κB signaling which maintains and/or upregulates TGF-β expression. Increased TGF-β levels upregulate CTLA-4 and GITR expression by Treg. CTLA-4 interacts with B7.1 (CD80) and B7.2 (CD86) on DC, resulting in the induction of IDO1 (in DC) and commensurate downregulation of antigen presentation to T cells. Both GBM and MDSC express TGF-β, which synergizes with PD-L1 to suppress the T cell effector response via interaction with PD-1. Moreover, interleukin-10 (IL-10)- and prostaglandin E2 (PGE2)-expressing MDSC act on their cognate receptors expressed by GBM to ramify Jak/STAT and NK-κB-mediated signaling. DNA released by dead/dying GBM cells is phagocytized by resident DC to activate the STING pathway leading to Type 1 interferon (α/β) expression, supporting increased effectiveness of anti-GBM immunity. PD-1 is highly expressed by tumor-infiltrating cytotoxic T cells and PD-L1 is upregulated on cancer/stromal cells in response to T-cell-secreted IFNγ. Blocking the interaction of PD-1-expressing T cells with PD-L1 leads to increased effector function and enhanced GBM immunity. Targets for immunomodulation are shown in red. Note: Although IDO1 expression and signaling are shown in GBM cells, shared signaling patterns are presumed to be present in DC and MDSC as well. T_CON: conventional CD4⁺FoxP3⁻ T cell; T_REG: regulatory CD4⁺FoxP3⁺ T cell; T_C: cytotoxic CD8⁺ T cell; INCBO24360/NLG919: inhibitors of IDO1; PS1145: inhibitor of the NF-κB pathway; TRX518: humanized monoclonal agonistic antibody for GITR; Ipilimumab: humanized monoclonal antibody for CTLA-4; LY2109761: TGF-β receptor kinase inhibitor; MK-3475/MDX-1106: humanized monoclonal antibodies to PD-1; MEDI4736/MPDL3280A: humanized monoclonal antibodies to PD-L1; Anti-Gr1: mSC-depleting antibody; Daclizumab: humanized anti-CD25 (IL-2Rα); STING: stimulator of interferon genes; TBK1: TANK-binding kinase 1; IRF3/7: interferon regulatory factor 3/7; STAT3: signal transducer and activator of transcription 3; A.