HGG-13. Determining Regional Differences in High-Grade Glioma Vasculature Phenotype

Wei, Xiao‐Hong; Hartley, Rachel; Bear, Heather; Fuller, Christine; Phoenix, Timothy N.

doi:10.1093/neuonc/noz036.107

Cited by 3 publications

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“…Their analysis found that H3-WT gliomas had a significant enrichment in endothelial gene signatures compared to H3-mutated pHGGs, suggesting increased vascularization of H3-WT tumors. This hypothesis is being investigated using mouse models of DIPG and pHGG [18]. They also found that tumors rich in antigen-presenting cells (APCs), such as dendritic cells and helper T-cells, had a favorable prognosis if the tumor also contained cytolytic cells (CD8 T-cells and NK).…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that local neuroinflammation caused by infused CAR-T therapy was shown to be fatal in mouse models [23], indicating that caution must be used when attempting to stimulate cytokines in brainstem pHGGs. Another cogent hypothesis is that vascular differences exist between these tumor locations [17,18,24], preventing the influx of immune cells to the tumor site. Our data showing mast cell and eosinophil associations with tumors are surprising.…”

Section: Discussionmentioning

confidence: 99%

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Computational immune infiltration analysis of pediatric high‐grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location

et al. 2021

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Immunotherapy for cancer has moved from pre-clinical hypothesis to successful clinical application in the past 15 years. However, not all cancers have shown response rates in clinical trials for these new agents. igh-grade gliomas, in particular, have proved exceedingly refractory to immunotherapy. In adult patients, there has been much investigation into these failures, and researchers have concluded that an immunosuppressive microenvironment combined with low mutational burden renders adult glioblastomas "immune cold." Pediatric cancer patients develop gliomas at a higher rate per malignancy than adults, and their brain tumors bear even fewer mutations. These tumors can also develop in more diverse locations in the brain, beyond the cerebral hemispheres seen in adults, including in the brainstem where critical motor functions are controlled. While adult brain tumor immune infiltration has been extensively profiled from surgical resections, this is not possible for brainstem tumors that can only be sampled at autopsy. Given these limitations, there is a dearth of information on immune cells and their therapeutic and prognostic impact in pediatric high-grade gliomas (pHGGs), including hemispheric tumors in addition to brainstem. In this report, we use computational methods to examine immune infiltrate in pHGGs and discover distinct immune patterns between hemispheric and brainstem tumors. In hemispheric tumors, we find positive prognostic associations for regulatory T-cells, memory B-cells, eosinophils, and dendritic cells, but not in brainstem tumors. These differences suggest that immunotherapeutic approaches must be cognizant of pHGG tumor location and tailored for optimum efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Computational immune infiltration analysis of pediatric high‐grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location

et al. 2021

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Highlights in targeted nanoparticles as a delivery strategy for glioma treatment

Luiz

Filippo

Tofani

et al. 2021

International Journal of Pharmaceutics

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Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma

et al. 2020

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Background Diffuse midline gliomas (DMG), including brainstem diffuse intrinsic pontine glioma (DIPG), are incurable pediatric high-grade gliomas (pHGG). Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) is clinically relevant but has not been carefully investigated in pHGG or DIPG. Methods Patient-derived DIPG cell lines, orthotopic mouse models, and pHGG datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells pretreated with LSD1 inhibitors, and informatics platforms were used to determine immune infiltration of pHGG. Results Selective cytotoxicity and an immunogenic gene signature were established in DIPG cell lines using clinically relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit of this LSD1-dependent gene signature. Pretreatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. Catalytic LSD1 inhibitors induced tumor regression and augmented NK cell infusion in vivo to reduce tumor burden. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival, while CD8 T cells are negatively prognostic. Catalytic LSD1 inhibitors are nonperturbing to NK cells, while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells. Conclusions LSD1 inhibition using catalytic inhibitors is selectively cytotoxic and promotes an immune gene signature that increases NK cell killing in vitro and in vivo, representing a therapeutic opportunity for pHGG. Key Points 1. LSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG and shows in vivo efficacy as a single agent. 2. An LSD1-controlled gene signature predicts survival in pHGG patients and is seen in neural tissue from LSD1 inhibitor–treated mice. 3. LSD1 inhibition enhances NK cell cytotoxicity against DIPG in vivo and in vitro with correlative genetic biomarkers.

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HGG-13. Determining Regional Differences in High-Grade Glioma Vasculature Phenotype

Cited by 3 publications

References 0 publications

Computational immune infiltration analysis of pediatric high‐grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location

Computational immune infiltration analysis of pediatric high‐grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location

Highlights in targeted nanoparticles as a delivery strategy for glioma treatment

Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma

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