Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.

Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs are associated with tumor-mediated education yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDMs in primary and metastatic disease in mouse and human

Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells

Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high-grade gliomas and brain metastases (BrMs) originating from diverse extracranial tumors. Our understanding of the brain tumor microenvironment (TME) remains limited, and it is unknown whether it is sculpted differentially by primary versus metastatic disease. We therefore comprehensively analyzed the brain TME landscape via flow cytometry, RNA sequencing, protein arrays, culture assays, and spatial tissue characterization. This revealed disease-specific enrichment of immune cells with pronounced differences in proportional abundance of tissue-resident microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells. These integrated analyses also uncovered multifaceted immune cell activation within brain malignancies entailing converging transcriptional trajectories while maintaining disease- and cell-type-specific programs. Given the interest in developing TME-targeted therapies for brain malignancies, this comprehensive resource of the immune landscape offers insights into possible strategies to overcome tumor-supporting TME properties and instead harness the TME to fight cancer

Updated survival data of the phase iii clinical trial of novottf-100a versus best standard chemotherapy for recurrent glioblastoma

NovoTTF-100A (TTF) is a portable device delivering low-intensity, intermediate-frequency, alternating electric fields using noninvasive, disposable scalp electrodes. TTF interferes with tumor cell division, and it has been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent glioblastoma (rGBM) based on data from a phase III trial. This presentation describes the updated survival data 2 years after completing recruitment. Adults with rGBM (KPS ≥ 70) were randomized (stratified by surgery and center) to either continuous TTF (20-24 h/day, 7 days/week) or efficacious chemotherapy based on best physician choice (BPC). The primary endpoint was overall survival (OS), and secondary endpoints were PFS6, 1-year survival, and QOL. Patients were randomized (28 US and European centers) to either TTF alone (n ¼ 120) or BPC (n ¼ 117). Patient characteristics were balanced, median age was 54 years (range, 23-80 years), and median KPS was 80 (range, 50-100). One quarter of the patients had debulking surgery, and over half of the patients were at their second or later recurrence. OS in the intent-to-treat (ITT) population was equivalent in TTF versus BPC patients (median OS, 6.6vs. 6.0 months; n ¼ 237; p ¼ 0.26; HR ¼ 0.86). With a median follow-up of 33.6 months, long-term survival in the TTF group was higher than that in the BPC group at 2, 3, and 4 years of follow-up (9.3% vs. 6.6%; 8.4% vs. 1.4%; 8.4% vs. 0.0%, respectively). Analysis of patients who received at least one treatment course demonstrated a survival benefit for TTF patients compared to BPC patients (median OS, 7.8 vs. 6.0 months; n ¼ 93 vs. n ¼ 117; p ¼ 0.012; HR ¼ 0.69). In this group, 1-year survival was 28% vs. 20%, and PFS6 was 26.2% vs. 15.2% (p ¼ 0.034). TTF, a noninvasive, novel cancer treatment modality shows significant therapeutic efficacy with promising long-term survival results. The impact of TTF was more pronounced when comparing only patients who received the minimal treatment course. A large-scale phase III trial in newly diagnosed GBM is ongoing