Amy Heimberger

• Research Director at Northwestern University

Gliomas are the most common primary malignant brain tumors. Their electrobiologic properties drive disease development, and in select tumors, aberrant neurosignaling is situated at the crux of gliomagenesis and glioma-related epilepsy (GRE). Tumor microtubes and the neuronal-glioma synapse are defined components of the glioma circuitry. The nidus o...

INTRODUCTION Histologic findings are the primary determinant of meningioma prognosis and post-operative management. However, the relationship of specific pathologic features to molecular alterations has not yet been comprehensively investigated. METHODS Detailed histological information was collected for 809 resected meningiomas, including cases w...

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro- tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patie...

Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, characterized by heterogeneity and aggressive tumor growth. The identification of novel biomarkers and therapeutic targets is crucial for advancing promising therapies. This study profiled patient-derived tumor samples utilizing single-cell RNA sequencing and proteomics platforms...

Sequential multiplex methodologies such as Akoya CODEX, Miltenyi MACSima, Rarecyte Orion, and others require modification of the antibodies by conjugation to an oligo or a specific fluorophore which means the use of off-the-shelf reagents is not possible. Modifications of these antibodies are typically performed via reduction chemistry and thus req...

The blood–brain barrier is a physiological barrier that can prevent both small and complex drugs from reaching the brain to exert a pharmacological effect. For treatment of neurological diseases, drug concentrations at the target site are a fundamental parameter for therapeutic effect; thus, the blood–brain barrier is a major obstacle to overcome....

Purpose: A glioblastoma (GBM) is a primary brain tumor with significant unmet therapeutic needs. Immune checkpoint inhibitors (ICIs) have marked therapeutic benefits in many different cancers but have yet to show benefit for most GBM patients in phase III trials. Methods: A systematic review querying ClinicalTrials.gov for prospective clinical tria...

Tumor-associated myeloid cells (TAMCs) promote immunosuppression in the GBM tumor microenvironment (TME) and resistance to immune checkpoint therapy (ICT). However, the metabolic and epigenetic mechanisms underlying TAMC activation and the therapeutic potential of fine-tuning TAMC activation remain largely unexplored. Our analyses of GBM patient si...

Glioblastoma harbors a tumor microenvironment (TME) that is mostly devoid of T cell effector infiltration but is dominated by immune suppressive microglia, macrophages, and myeloid-derived suppresser cells. The innate immune cells in the TME have impaired phagocytosis and antigen presentation and are inadequate for triggering the subsequent immune...

BACKGROUND Approximately 30 to 50% of patients with glioblastoma (GBM) present with glioma-related epilepsy (GRE). Despite morbidity associated with seizures, GRE constitutes an independent positive predictive predictor for survival in GBM. Our prior results showed that repeated seizure induction through extrinsic electrical modulation (EEM, a tech...

Histologic findings are the primary determinant of meningioma prognosis and post-operative management. However, the association of specific pathologic features with molecular alterations has not yet been comprehensively investigated. Here we utilized a large dataset of well-characterized meningiomas to identify correlates between clinically relevan...

Glioblastoma (GBM) is an incurable primary malignant neoplasm of the central nervous system. GBM as an electrically active neoplasm diffusely colonizes healthy brain tissues, disrupting the neurotransmission balance and causing glioma-related epilepsy (GRE) in up to 50% of patients. Interestingly, GRE is an independent favorable prognostic factor f...

Brain invasion is a negative prognostic factor for meningiomas, but the molecular programs underlying meningioma brain invasion are poorly understood. To address this, we performed transcriptomic analyses of 3 independent datasets: Bulk RNA sequencing from 199 meningiomas (n=33 with brain invasion), single-cell RNA sequencing of 2 regionally distin...

Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for lesions that are intractable to surgery and radiation. To identify novel treatment approaches, scRNA-sequencing datasets were reanalyzed from thirteen meningiomas and nine adjacent dura samples including >30,000...

Glioblastoma (GBM) presents as a highly aggressive and malignant brain tumor with limited treatment options. Despite the availability of existing therapies, the invasive characteristics of GBM frequently result in tumor recurrence and poor prognosis. We previously developed a B-cell-based therapy (BVax) that has shown promising results in its abili...

STING (stimulator of interferon genes) activation triggers interferon (IFN) release within the tumor microenvironment from myeloid cells and other cell types, inducing proinflammatory anti-tumor immune responses. The small molecule STING agonist, 8803, elicits long-term survival in 56% (QPP4; p=0.0003) to 100% (QPP8; p<0.0001) of mice with orthotop...

Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied. Repurposing of adult brain tumor immunotherapies in pediatric patients has not been successful, highlighting the need for pediatric-specific immunotherapies. Pilocytic astrocytomas (PA) are the most common pediatric glioma. While surgical re...

Background Glioblastoma harbors a tumor microenvironment (TME) that is mostly devoid of effector T cells but is dominated by immunosuppressive microglia, macrophages, and myeloid-derived suppresser cells. Innate immune cells in the TME have impaired phagocytosis and antigen presentation and are inadequate for triggering the immune activating signal...

Background Targeting the cGAS-STING (cyclic GMP-AMP synthase-Stimulator of Interferon Genes) pathway with cyclic dinucleotides (CDNs) offers a promising immunotherapeutic strategy for lymphocyte-depleted, myeloid cell-enriched solid tumors like Glioblastoma (GBM). However, this approach is constrained by the limited bioavailability of CDNs and the...

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate...

Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics a...

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the Bvax (B-...

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could...

Background Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. Methods In this study, we used sequential single-cell transcriptomics on 144,678 and spectral cytometry on over two million immune cells en...

Background Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in “cold” and immunotherapy-refractory cancers. Method We evaluated the efficacy and immune microenvironment phenotype of a mouse analogu...

BACKGROUND The immune microenvironment of pediatric gliomas is relatively understudied despite being a leading cause of childhood mortality. Pilocytic astrocytomas (PA) are the most common pediatric glioma and surgical resection is often curative. However, PAs are not always amenable to surgery and can have significant long-term morbidity and morta...

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in mult...

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play a crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome in cancer cells reprograms the immune landscape within the tumor microenvironment, thereby hindering antitumor immunity, promoting tumor...

Although myeloid-derived immune cells can be dispersed throughout the tumor microenvironment (TME), anti-tumor effector cells are confined to the perivascular space. Here, we present a protocol to quantify immune cell distribution from tumor vasculature to its glioma microenvironment on sequential immunofluorescence multiplex images. We describe st...

Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spat...

Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and r...

Macrophages and microglia are professional phagocytes that sense and migrate toward “eat-me” signals. The role of phagocytic cells is to maintain homeostasis by engulfing senescent or apoptotic cells, debris, and abnormally aggregated macromolecules. Usually, dying cells send out “find-me” signals, facilitating the recruitment of phagocytes. Health...

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. T...

Simple Summary Meningiomas are the most common intracranial tumors, and significant advances have been made in our understanding of the biology that leads to meningioma growth and aggressiveness. This review summarizes molecular advances and the historical contexts that led to them. Abstract Meningioma classification and treatment have evolved ove...

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating ant...

Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of...

Understanding the spatial relationship and functional interaction of immune cells in glioblastoma (GBM) is critical for developing new therapeutics that overcome the highly immunosuppressive tumor microenvironment. Our study showed that B and T cells form clusters within the GBM microenvironment within a 15-μm radius, suggesting that B and T cells...

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal m...

Fares et al. identified metixene as an NDRG1-mediated incomplete autophagy inducer that reduces tumor size and increases survival in models of metastatic breast cancer and brain metastases. The cover art depicts a metastatic cancer cell (red) being targeted by metixene (blue). Image credit: Jawad Y. Fares.

Despite the recent success of immune checkpoint blockade in various cancer types, glioblastoma (GBM) remains resistant to immunotherapy due to its immunosuppressive features and the poor penetration of systemic agents across the blood-brain barrier (BBB). Recent clinical trials demonstrated the unprecedented efficacy of Fc enhanced anti-CTLA-4, an...

Using an in vivo CRISPR screen approach, we demonstrated the contribution of glioma cell intrinsic checkpoint kinase 2 (Chek2) in the evasion of tumor cells from CD8+ T cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are being evaluated in clinical trials, in combination with...

In a phase I clinical trial for patients with recurrent glioblastoma, we used an implantable ultrasound device for low-intensity pulsed ultrasound and microbubbles (LIPU/MB) to open the blood-brain barrier (BBB). This strategy increased parenchymal drug concentrations by 3.7- to 5.9-fold. Magnetic resonance imaging analysis with gadolinium injectio...

BACKGROUND Immune checkpoint inhibitors (CPI) have failed to show survival benefit in glioblastoma. Understanding the alterations in the tumor microenvironment after treatment with CPI is crucial for development of immunotherapy in glioblastoma. We previously reported our window-of-opportunity trial of pembrolizumab in GBM (NCT02337686). In the cur...

Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of c...

MGMT promoter methylation predicts favorable temozolomide (TMZ) response in gliomas. Accurate test results depend on adequate tumor cellularity in analyzed samples, which is usually estimated (with sub-optimal accuracy) via light microscopy. We evaluated driver mutation variant allelic frequency (VAF) as a quantitative metric for tumor cellularity...

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellul...

Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternativ...

Background Malignant gliomas (MG) are rapidly fatal despite multimodal treatments including radiation therapy, used to treat nearly all MG patients, or even the emerging cellular immunotherapies. Therapeutic resistance in glioma is at least partly related to tolerogenic STAT3 activity in both glioma cancer stem cells (GCSs) and in the tumor-associa...

This Special Issue focuses on the evolving role of immune modulatory cytokines, from their initial use as monotherapeutic recombinant proteins to their more contemporaneous use as modifiers for adoptive cellular immunotherapy [...]

A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a central nervous system (CNS) small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the U.S. Food and Drug Administration, breast cancer brain metastases vulnerabili...

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators...

Plain language summary Cancer of the esophagus, the tube that connects the mouth to the stomach, tends to be aggressive. Very rarely, this cancer can spread to the lining that surrounds your brain, called the leptomeninges. Previous reports of patients who have experienced this specific spreading pattern of esophageal cancer to the leptomeninges ar...

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3cm, smaller lesions (≤3cm) undergo SRS alone with variable responses. To determi...

Background There is immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older. Methods NUTMEG was a multicenter 2:1 randomized phase II trial for...

Simple Summary Despite multi-modal treatment consisting of surgery, chemotherapy, and radiation, glioblastoma inevitably recurs due to its diffuse infiltrative nature. Anti-tumor immune responses, supported by pro-inflammatory cytokines, that can seek out remote cancer vestiges will likely become part of the therapeutic armamentarium but will requi...

Simple Summary Pediatric brain tumors are unique from adult tumors and pose challenges due to their distinct characteristics, including differences in tumor immunology, molecular profiles, and response to various treatments. Understanding these differences is crucial for developing targeted and effective therapeutic strategies. This review delves i...

Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas, and the cell types and signaling mechanisms driving meningioma tumorigenesis or resi...

PURPOSE To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG). METHODS Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and characterize the tumor microenvironment (TME) of 13 new...

Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here we describe what we believe to be a new...

2066 Background: The frequency and expression of predictive immune biomarkers in pediatric gliomas is relatively unknown. Here, we sought to define predictive signatures of immunotherapy responders by examining immune checkpoint expression, immune cell population signatures, and gene amplifications in a variety of pediatric gliomas. Methods: We pro...

2039 Background: Brain metastases occur in multiple cancer types with higher prevalence in lung, breast, melanoma, and GI cancers. The prognoses of patients who develop brain metastases are very poor and identification of brain metastasis risk could be useful for prognostication, monitoring, and therapy selection. Methods: Data from the whole trans...

3078 Background: The diagnosis of a malignancy is typically informed by clinical presentation and tumor tissue features including cell morphology, immunohistochemistry, and molecular markers. Additionally, multi-omic approaches (Abraham 2021 Transl Oncol) and deep learning models using digital pathology (da Silva 2021 J Pathol) have augmented exper...

Intratumor heterogeneity underlies cancer evolution and treatment resistance 1–5 , but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all current medical therapies 6,7 . High-grade meningiomas cause significant neurological morbidity and...

Fibrinogen-like protein 1 (FGL1) has been associated with improved survival in hepatocellular carcinoma (HCC). However, recent evidence suggests that FGL1 may bind to surface receptors on lymphocytes and induce immune senescence. In this issue of the JCI, Lin and co-authors show that FGL1 may be acetylated by aspirin and targeted for degradation, w...

Introduction Immune surveillance, distribution, interactions, and antigen presentation within the tumor microenvironment (TME) may influence anti-tumor reactivity and survival. Methods Dichotomized newly diagnosed treatment-naïve IDH1 wild-type glioblastoma, negative MGMT promotor methylation (65%), short-term (STS; ≤ 6 months; mean age 66 years;...

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated wi...

Purpose: Trials of immunotherapy in diffuse glioma patients have been mostly unsuccessful. We therefore sought to determine the combined effects of the signal transducer and activator of transcription 3 (STAT3) inhibitor WP1066 and the STING agonist IACS-8803 in a preclinical model of glioma. Experimental Design: C57BL/6 mice (n=9-10/group) with or...

Gliomas are recalcitrant brain tumors. Differential tumor immune reactivity contributes to survival advantage of isocitrate dehydrogenase-mutant (IDHmut) over wild-type (IDHwt) gliomas. Despite this correlative pattern of immunity and survival, only a limited view of a highly complex immune contexture across IDH mutation classified gliomas is known...

INTRODUCTION Genome-wide methylation profiling has emerged as a transformative prognostic tool in meningiomas, and has identified discrete epigenetic clusters that share distinct clinical and biological features. The association of these signatures with underlying pathological mechanisms has not been well-explored. METHODS From a collection of ove...

Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cell mediated killing are less understood. Kinases are potentially druggable targets that drive tumor progression and might influence immune response. Here, we perfor...

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (...

Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epiderm...

Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hal...

Background: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We therefore developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblast...

Immunotherapy has emerged as a powerful strategy for halting cancer progression. However, primary malignancies affecting the brain have been exempt to this success. Indeed, brain tumors continue to portend severe morbidity and remain a globally lethal disease. Extensive efforts have been directed at understanding how tumor cells survive and propaga...

Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. N...

Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad...

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system and contains a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME that contribute to most GBM hallmarks, including immunosuppression. The understanding of TAMs i...

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature o...

Venous thromboembolism (VTE) is a life-threatening condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma p...

DNA methylation profiling has emerged as a transformative prognostic tool in meningiomas, identifying distinct epigenetic subgroups that share unique clinical and biological features. Hypothesizing that methylation patterns may also reflect underlying pathogenic mechanisms, we investigated if this modality could be informative for the selection of...

Venous thromboembolism (VTE) is a common paraneoplastic complication in patients with adult-type diffuse gliomas. VTE greatly diminishes quality-of-life, and can even be life-threatening. While effective VTE prediction models exist for other cancers, those models do not work for gliomas. Thus, there are no standard guidelines for thromboprophylaxis...

BACKGROUND Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients...

OBJECTIVE Previous work indicates poorer survival outcomes for older glioblastoma (GBM) patients ≥ 65 years of age as compared to younger patients < 65 years of age. The cellular mechanisms associated with this age-dependent survival difference remain elusive. Here we evaluated the overall survival of young and old immunocompetent mice with intracr...

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...

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of myeloid and lymphoid cell type diversit...

Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in precl...

Background Gliomas are recalcitrant brain tumors. Anti-glioma immunity and immunopathogenic responses are critical contributors for better survival of isocitrate dehydrogenase-mutant (IDHmut) over wild-type (IDHwt) gliomas. Despite this correlative pattern of immunity and survival, an unbiased understanding of cell-type specific transcriptomic and...

Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial‐mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 s...

Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells...

Brain tumors are among the 10 leading causes of cancer-related death and present unique treatment challenges due to their critical location and genetic heterogeneity and the blood-brain barrier. Recent advances in targeted immunotherapy and immune checkpoint blocking therapy provide alternative therapeutic strategies for brain tumors. Fibrinogen-li...