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Genes May 2023Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer-related death among women. Brain metastases are a primary contributor... (Review)
Review
Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer-related death among women. Brain metastases are a primary contributor to mortality, as they often go undetected until late stages due to their dormant nature. Moreover, the clinical management of brain metastases is complicated by the relevant issue of blood-brain barrier penetration. The molecular pathways involved in the formation, progression, and colonization of primary breast tumors and subsequent brain metastases are diverse, posing significant hurdles due to the heterogeneous nature of breast cancer subtypes. Despite advancements in primary breast cancer treatments, the prognosis for patients with brain metastases remains poor. In this review, we aim to highlight the biological mechanisms of breast cancer brain metastases by evaluating multi-step genetic pathways and to discuss currently available and emerging treatment strategies to propose a prospective overview of the management of this complex disease.
Topics: Female; Humans; Breast Neoplasms; Prospective Studies; Brain Neoplasms; Prognosis; Breast
PubMed: 37372340
DOI: 10.3390/genes14061160 -
Oncogene Jun 2023Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to... (Review)
Review
Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 37277603
DOI: 10.1038/s41388-023-02738-y -
Cancer Cell Aug 2023Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its...
Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Topics: Humans; Glioblastoma; Thromboplastin; Cell Line, Tumor; Neoplasm Recurrence, Local; Signal Transduction; Brain Neoplasms; Tumor Microenvironment
PubMed: 37451272
DOI: 10.1016/j.ccell.2023.06.007 -
Cancer Cell Jun 2023Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature,...
Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1CD8 stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.
Topics: Mice; Animals; Glioma; Brain Neoplasms; Glioblastoma; Phenotype; Brain; Tumor Microenvironment
PubMed: 37172581
DOI: 10.1016/j.ccell.2023.04.010 -
The Journal of Clinical Investigation Sep 2023In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well...
In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.
Topics: Humans; Immune Checkpoint Inhibitors; Brain Neoplasms; Gene Expression Profiling; Glioblastoma; Macrophages; Tumor Microenvironment
PubMed: 37655659
DOI: 10.1172/JCI169314 -
Cancer Discovery Jul 2023Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional...
UNLABELLED
Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities-H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.
SIGNIFICANCE
Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting. See related commentary by Lubanszky and Hawkins, p. 1516. This article is highlighted in the In This Issue feature, p. 1501.
Topics: Animals; Mice; Histones; Gene Expression Regulation, Neoplastic; Glioma; Brain Neoplasms; Brain; Mutation
PubMed: 37011011
DOI: 10.1158/2159-8290.CD-23-0004 -
Science Translational Medicine May 2023Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and...
Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF/PTEN and BRAF/PTEN mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC-releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
Topics: Animals; Mice; Granulocyte-Macrophage Colony-Stimulating Factor; Gene Editing; Proto-Oncogene Proteins B-raf; Melanoma; Simplexvirus; Oncolytic Virotherapy; Oncolytic Viruses; Brain Neoplasms; Brain; Immunotherapy; Stem Cells; Melanoma, Cutaneous Malignant
PubMed: 37256936
DOI: 10.1126/scitranslmed.ade8732 -
Journal of Thoracic Oncology : Official... Aug 2023In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up.
METHODS
Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only).
RESULTS
Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed.
CONCLUSIONS
With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.
Topics: Adult; Humans; Nivolumab; Ipilimumab; B7-H1 Antigen; Lung Neoplasms; Neoplasm Recurrence, Local; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37146754
DOI: 10.1016/j.jtho.2023.04.021 -
Neuro-oncology Jun 2023Gliomas are the most common type of central nervous system tumors in children, and the combination of histological and molecular classification is essential for...
BACKGROUND
Gliomas are the most common type of central nervous system tumors in children, and the combination of histological and molecular classification is essential for prognosis and treatment. Here, we proposed a newly developed microstructural mapping technique based on diffusion-time-dependent diffusion MRI td-dMRI theory to quantify tumor cell properties and tested these microstructural markers in identifying histological grade and molecular alteration of H3K27.
METHODS
This prospective study included 69 pediatric glioma patients aged 6.14 ± 3.25 years old, who underwent td-dMRI with pulsed and oscillating gradient diffusion sequences on a 3T scanner. dMRI data acquired at varying tds were fitted into a 2-compartment microstructural model to obtain intracellular fraction (fin), cell diameter, cellularity, etc. Apparent diffusivity coefficient (ADC) and T1 and T2 relaxation times were also obtained. H&E stained histology was used to validate the estimated microstructural properties.
RESULTS
For histological classification of low- and high-grade pediatric gliomas, the cellularity index achieved the highest area under the receiver-operating-curve (AUC) of 0.911 among all markers, while ADC, T1, and T2 showed AUCs of 0.906, 0.885, and 0.886. For molecular classification of H3K27-altered glioma in 39 midline glioma patients, cell diameter showed the highest discriminant power with an AUC of 0.918, and the combination of cell diameter and extracellular diffusivity further improved AUC to 0.929. The td-dMRI estimated fin correlated well with the histological ground truth with r = 0.7.
CONCLUSIONS
The td-dMRI-based microstructural properties outperformed routine MRI measurements in diagnosing pediatric gliomas, and the different microstructural features showed complementary strength in histological and molecular classifications.
Topics: Humans; Child; Child, Preschool; Brain Neoplasms; Prospective Studies; Neoplasm Grading; Glioma; Diffusion Magnetic Resonance Imaging
PubMed: 36617263
DOI: 10.1093/neuonc/noad003 -
Cancer Science Jun 2023Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which...
Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, glioblastoma remains refractory to treatment and recurrence is inevitable. Moreover, the biology of recurrent glioblastoma remains unclear. Increasing evidence has shown that intratumoral heterogeneity and the tumor microenvironment contribute to therapeutic resistance. However, the interaction between intracellular heterogeneity and drug resistance in recurrent GBMs remains controversial. The aim of this study was to map the transcriptome landscape of cancer cells and the tumor heterogeneity and tumor microenvironment in recurrent and drug-resistant GBMs at a single-cell resolution and further explore the mechanism of drug resistance of GBMs. We analyzed six tumor tissue samples from three patients with primary GBM and three patients with recurrent GBM in which recurrence and drug resistance developed after treatment with the standard Stupp protocol using single-cell RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation of the expression of stemness-related and cell-cycle-related genes was observed in recurrent GBM cells. Compared with the initial GBM tissues, recurrent GBM tissues showed a decreased proportion of microglia, consistent with previous reports. Finally, vascular endothelial growth factor A expression and the blood-brain barrier permeability were high, and the O -methylguanine DNA methyltransferase-related signaling pathway was activated in recurrent GBM. Our results delineate the single-cell map of recurrent glioblastoma, tumor heterogeneity, tumor microenvironment, and drug-resistance mechanisms, providing new insights into treatment strategies for recurrent glioblastomas.
Topics: Humans; Glioblastoma; Vascular Endothelial Growth Factor A; Brain Neoplasms; Drug Resistance; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 36853018
DOI: 10.1111/cas.15773