Synergy between glutamate modulation and anti–programmed cell death protein 1 immunotherapy for glioblastoma

Abstract

OBJECTIVE Immune checkpoint inhibitors such as anti–programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression

“…We showed that the inclusion of riluzole, an inhibitor of glutamate export, and/or CB-839, an inhibitor of glutaminase, in the growth media led to a reduction in cell growth and subsequent tumor progression in vitro and in vivo [ 39 , 68 ]. The application of riluzole has shown promise in melanoma, breast cancer, glioma, prostate cancer, and kidney cancer [ 39 , 89 , 97 , 101 , 119 , 121 , 177 , 178 , 179 ]. Our lab and others have provided pre-clinical data that support the combination of riluzole/troriluzole with different therapeutic approaches that target different oncogenic pathways: oxidative stress/genomic instability (γ-radiation therapy or PARP inhibitors), cell metabolism (CB-839), and angiogenesis/metastasis (anti-VEGF treatments or inhibitors for exosome biogenesis and secretion) [ 28 , 57 , 68 , 69 , 119 , 178 , 179 , 180 , 181 , 182 , 183 ].…”

“…In glioblastoma, there are high levels of circulating glutamate that stimulate mGluRs to support tumor progression [ 91 ]. Furthermore, riluzole treatment reduces the aggressiveness of glioma cells [ 119 , 121 ]. One of the known functions of riluzole is the inhibition of glutamate release into the extracellular environment.…”

Effect of Nanoparticles of DOX and miR-125b on DNA Damage Repair in Glioma U251 Cells and Underlying Mechanisms

“…Its main functions include regulating the activation of checkpoints under DNA double-strand break or oxidative stress and coordinating DNA repair, cell cycle progression, and cell metabolism [ 18 ]. The pathogenic germline mutations of ATM play a role in DNA damage reactions and cell cycle checkpoints, so ATM has now become an important marker of cancers and a new target for cancer treatment [ 19 ]. Histones play a pivotal role in the composition and gene function regulation of chromatin structures in eukaryotes.…”

Metabolic reprogramming and signalling cross-talks in tumour–immune interaction: a system-level exploration

“…In addition to these targets in tumour cells, metabolic alterations in immune cells were also studied previously. Evidence suggests that immunosuppression caused by glutamate release from glioma can be mitigated by regulating glutamate levels in T-cells [ 9 , 10 ]. In addition, succinate regulating the pro-inflammatory response of macrophages was also studied previously [ 11 ].…”