Monday, November 14, 2022

TMIC-19. NEURODEVELOPMENTAL SUBTYPES SHAPE LIPID METABOLIC REPROGRAMMING IN GLIOMAS

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Abstract
Gliomas have been classified into molecular (proneural, classical, mesenchymal) and neurodevelopmental (astrocyte, mesenchymal, neural progenitor cell (NPC), oligodendrocyte progenitor cell (OPC)) subtypes describing inter- and intra-tumoral heterogeneity; however, the functional outcomes and therapeutic implications of these subtypes has yet to be fully described. Metabolic reprogramming is a hallmark of cancer, and malignant cells, including gliomas, acquire metabolic adaptations in response to a multitude of intrinsic (oncogenotype, mutations) and extrinsic (tumor microenvironment) factors to fuel neoplastic progression. Altered metabolism in glioma is of particular interest given the extensive molecular heterogeneity of tumors, while also developing in the brain microenvironment, a tissue known for its unique metabolic milieu. It is unknown whether neurodevelopmental subtypes influence metabolism in gliomas. Preliminary comprehensive lipidomi c and transcriptomic analysis of over 200 patient-derived glioma samples revealed that distinct lipid signatures were linked to neurodevelopmental subtypes. Specifically, proneural-like gliomas (OPC, NPC, Neuron) had a lipid metabolic profile enriched in ether lipids. Conversely, mesenchymal-like gliomas (radial glia, MES.progenitor, vascular) have a lipid metabolic profile enriched in triacylglycerides (TAGs). Intriguingly, these differences in lipid metabolic programs between subtypes were associated with environmental dependencies; in contrast to more mesenchymal like gliomas, which could grow irrespective of tumor microenvironment (brain or in vitro cell culture), the proneural-like gliomas required features of the brain microenvironment to accumulate complex fatty acids and grow. Collectively, these data emphasize the metabolic heterogeneity within gliomas, and reveal a subset of gliomas that lack metabolic plasticity in fatty acid biosynthetic programs, indicating a potential brain-microenvironment specific metabolic dependency linked to transcriptional identity that may be targeted for therapy.
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CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME

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Abstract
BACKGROUND
Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/
METHODS
Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemot herapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle).
RESULTS
Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18).
CONCLUSIONS
Indoximod was well tolerated and could be combined with a var iety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.
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EPCO-28. DOT1L AND PRC2 REGULATE A SHARED EPIGENETIC MECHANISM IN GLIOBLASTOMA AND MIXED LINEAGE LEUKEMIA

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Abstract
Glioblastoma (GBM) is the most aggressive adult brain tumor, with a median survival of 15 months despite current treatments. We recently established that the epigenetic regulator Disruptor of Telomeric Silencing-1-Like (DOT1L) was essential for the growth of brain tumor stem cells (BTSCs), which are thought to underlie GBM tumor initiation and treatment resistance. Given the previously recognized importance of DOT1L histone methylation for the regulation of the similarly rare and aggressive childhood cancer, Mixed Lineage Leukemia (MLL), we interrogated for common mechanisms in both BTSCs and MLL cells, that overlap due to the epigenetic role of DOT1L. To gain a more detailed perspective of the importance of the DOT1L epigenetic mark in BTSCs, we performed a chemogenomic screen using the DOT1L inhibitor, EPZ-5676. Results from this screen revealed genes from transcriptional and epigenetic complexes required for a therapeutic response to DOT1L inh ibition in BTSCs. Gene targeting approaches and growth assays further identified the Polycomb Repressive Complex 2 (PRC2) as a common determining factor for the growth response of both BTSCs and MLL cells following DOT1L inhibition. Furthermore, analysis of the chromatin accessibility changes regulated by DOT1L and PRC2 histone methylation identified both shared and unique epigenetic characteristics of GBM and MLL. The extent to which these shared mechanisms underpin the pathogenic process in these distinct diseases is being further investigated by assessing the divergence in transcriptional responses that emerge from this common epigenetic phenomenon. The findings from this study will provide insight into the importance of shared epigenetic mechanisms that underlie the tumorigenesis of unique cancers affecting the brain and blood.
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NCMP-10. NEURO-OPHTHALMOLOGICAL FINDINGS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA - A RETROSPECTIVE ANALYSIS

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Abstract
BACKGROUND
Medulloblastoma represents the most common malignant pediatric brain tumor. Ophthalmic complications are possible sequelae.
METHODS
Pediatric medulloblastoma (MB) patients treated at the Medical University of Vienna from January 2012 to August 2021 were analyzed and their last ophthalmic assessment was reviewed.
RESULTS
Fifty-six MB patients could be included (71.4% non-WNT/non-SHH, 16.1% SHH-activated, 8.9% WNT-activated, 3.6% non-specified). Mean age at diagnosis was 7.2 years (range 0-19). Median follow-up to last ophthalmological assessment was 19.7 months (range 0.1-93.2). Thirty-four children underwent tumor resection at our hospital, their tumor localizations were: vermis (55.9%), floor of the 4th ventricle (26.5%), cerebellar hemispheres (11.8%), lateral recess (5.9%). Symptoms at presentation were evaluable for 51 children: 92.2% had symptoms of elevated intracranial pressure, 76.5% ataxi a and 21.6% visual disturbances. Postoperative posterior fossa syndrome was observed in 11.1% of 54 children. 98.2% had chemotherapy as part of their initial treatment and all children older than four years (85.7%) received postoperative irradiation of the posterior fossa. In 13 (23.2%) intraventricular chemotherapy was applied. At the last follow-up 21 patients experienced relapse after primary treatment. At the final assessment, frequent neuro-ophthalmological abnormalities included: oculomotor disturbance (75%), esotropia (35.7%) including abducens palsy (12.5%), other cranial nerve palsies (21.4%), horizontal gaze-evoked nystagmus (51.8%), spontaneous nystagmus (16.1%), ocular tilt reaction (21.4%), and optic disc abnormalities (14.3%). Good visual acuity (≥20/25) was maintained in 62.5% patients. Visual field and optical coherence tomography was successfully performed in 75% and 66.1% of patients, respectively. Optic pathway lesions were detected in 4 patients (7.1%), includi ng two cases with occipital metastases, one with optic nerve metastasis and one with leptomeningeal carcinomatosis. Orthoptic treatment with prisms and strabismus surgery was required in 14.3% and 7.7% of children, respectively.
CONCLUSION
Children with MB frequently suffer from neuro-ophthalmological late-effects. Regular monitoring is warranted to initiate appropriate management.
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CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS

alexandrossfakianakis shared this article with you from Inoreader
Abstract
BACKGROUND
Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors.
METHODS
Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively
RESULTS
Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannito l and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) < 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors.
CONCLUSION
Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.
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BIOM-34. MULTIPLEX PHENOTYPING OF EXTRACELLULAR VESICLES FOR ANALYSIS OF POTENTIAL BIOMARKERS IN GLIOBLASTOMA PATIENTS

alexandrossfakianakis shared this article with you from Inoreader
Abstract
INTRODUCTION
Extracellular vesicles (EVs) carry biological information from their cell of origin that is useful for non-invasive detection of tumor biomarkers and disease monitoring. In glioblastoma (GBM), blood circulating EVs are elevated and carry GBM-associated proteins. However, it is still challenging to analyze tumor derived EVs for translational purposes. Here, we used imaging flow cytometry (IFCM) as a robust strategy to perform phenotyping of EVs with GBM related surface markers in human plasma.
METHODS
EVs were isolated via differential ultracentrifugation from plasma of (a) 40 GBM patients, pre- and post-surgery, (b) 11matched GBM relapses and (c) 12 healthy donors (HD). EV sizes and concentrations were evaluated by NTA. EV markers (CD9,CD63 and CD81) together with glioma-related markers (integrin beta-1 [ITGB1], tenascin C [TNC], Profilin-1 [PFN1], CD44,GPNMB, SPARC, HLA-II or CD133) were analyzed by IFCM. EV perce ntages and objects/mL plasma were compared among the groups and correlated with clinical parameters.
RESULTS
CD9 was the predominant tetraspanin in all groups (15-96%), while CD63 had the lowest levels (0-33%) and the strongestdecrease in GBM patients after surgery (fold change [FC]=-5.4, p<0.01). Among the glioma-related markers, ITGB1 and TNC displayed the most significant differences between the analyzed groups, especially the double positives ITGB1+/CD63+and TNC+/CD63+, which decreased in patients after tumor removal (FC=-3.5 and -12, respectively; p<0.001). Meanwhile,ITGB1+/CD9+and TNC+/CD9+EVs exhibited the highest levels in GBM when compared to HD subjects (FC=8.6 and 17.4;p<0.001) and upon tumor recurrence (FC=3.7 and 10.9, respectively; p<0.01).
SUMMARY/CONCLUSION
We identified EV surface antigens with potential clinical utility as GBM biomarkers. Among them, we highlight ITGB1 and TNC as the most promising markers.
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TMIC-31. ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Glioblastoma (GBM) is a primary brain tumour with poor prognosis and limited treatment options. We previously demonstrated that arginine deprivation by ADI-PEG20 is effective in GBM tumors which are auxotrophic for arginine. We also reported that ADI-PEG20 has efficacy in arginine non-auxotrophic GBM when combined with radiation in the presence of an immune competent environment. Here, we present detailed mechanistic insight into our latter findings using multiplex Imaging Mass Cytometry (Fluidigm) and Spatial Transcriptomics (10x Genomics) of tumor samples treated with ADI-PEG20. ADI-PEG20 enhanced the expression on MHC class II on infiltrating CD11c+ dendritic cells and these cells colocalised specifically with CD4+ T cells. We also observed changes in the expression of PD-1/PD-L1 with ADI-PEG20 and this was further enhanced when ADI-PEG20 was combined with radiation. Moreover, combination therapy increased the expression of chemokines involved in immune cell recruitment and activation. Our findings demonstrate that arginine deprivation restores immune function in the tumor microenvironment of arginine non-auxotrophic GBM tumors and suggests that combinations with immunotherapies will further enhance efficacy for GBM tumors.
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TMIC-80. SPATIOTEMPORAL GENOMICS OF HUMAN MEDULLOBLASTOMA WITHIN SUBGROUPS

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Whereas evidences of single-cell studies have suggested the cellular diversity of medulloblastoma, the most common malignant brain tumor in childhood, the understanding of spatial status for specific cell populations and gene modules remains rudimentary. Herein, we comprehensively analyze single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling from 52 human medulloblastomas spanning four molecular subgroups, complemented with the bulk whole genome and RNA sequencing data across 300 samples. We comprehensively interrogated the composition of medulloblastoma microenvironment and spatially described the developmental trajectory from progenitor-like to differentiated malignant cells. Furthermore, distinct heterogeneity within molecular subgroups leads to the identification of twelve subtypes of medulloblastoma, which unfortunately lacks the cellular biology. By deciphering the copy number variation and transcriptio nal programs at single-cell resolution, we in-depth characterized medulloblastoma and mapped the activity of gene expression and transcription factor binding according to individual subtype. The WNT-β, SHH-γ, Group 3-β and Group 4-γ were observed in early differentiation stage. Harmony alignment revealed subtype-dependent modules recapitulated the neurodevelopmental gene enrichment, strongly correlating to clinical outcomes. Collectively, our findings provide spatiotemporally resolved insights into transcriptome and epigenome of twelve-subtype medulloblastoma allowing further refinement regarding clinical risk stratification strategies.
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EPCO-33. DIFFERENTIAL EXPRESSION OF AN ENDOGENOUS RETROVIRAL ELEMENT [HERV-K(HML-6)] IS ASSOCIATED WITH REDUCED SURVIVAL IN GLIOBLASTOMA PATIENTS

alexandrossfakianakis shared this article with you from Inoreader
Abstract
INTRODUCTION
Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known.Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications.Method:A custom workflow was used to quantify HERV expression in our cell lines of interest. Cell-line methylation was quantified using a custom script. We generated primers specific for the Human endogenous Mouse mammary tumor (MMTV)-Like virus 6 (HML-6 ). Visualization of RNA transcripts was performed using RNA-scope. Clinical data was obtained using the R package, TCGABiolinks.
RESULTS
The A172 cell line had significantly higher mean overall HERV expression relative to the M059J and H4 cell lines (p< 0.0001 for both). A172 cells had significantly lower mean number of CpG islands relative to M059J cells and H4 cells (p< 0.0001 for both). There was a significant inverse correlation between mean beta value and FC HERV expression (R=-0.57, p=0.01). qPCR confirmed robust expression of the HML-6 locus in cell culture and neurospheres. Elevated ERVK3-1 expression was associated reduced survival among IDHwt GBM patients (18.3 vs. 15.1 months, p=0.039). This was preserved among IDH mutant (IDHm) GBM as well (17.9 months vs. 14.0 months, p=0.0088).
CONCLUSION
In gliomas, HERV expression correlates with loss of DNA methylation at HERV loci. HML- 6 is overexpressed in highly invasive glioblastoma cell lines and patient-derived neurospheres. We have demonstrated a potential survival detriment associated with elevated expression of the HML-6 product, ERVK3-1.
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TMIC-78. CIRCADIAN REGULATOR CLOCK DRIVES IMMUNOSUPPRESSION IN GLIOBLASTOMA

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Abstract
The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSCs) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK–BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via the hypoxia-inducible factor 1-alpha (HIF1A) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162, and polarizes infiltrating microglia towards an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK–OLFML3–HIF1A–LGMN–CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T cell infiltration, activation and cytotoxicity, and synergizes with anti-PD1 therapy. In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial level and poor prognosis. Together, these findings uncover the CLOCK–OLFML3–HIF1A–LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for GBM patients.
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