Anna Flury and al.

The authors demonstrate that in a murine model of Alzheimer's disease (AD), a subpopulation of microglial cells exhibit a molecular profile signing an integrated stress response (ISR). This stress response program alone induces specific ultrastructural features, collectively referred to as "dark microglia", which are associated with synapse loss. Amplifying such a microglial ISR exacerbates synaptic loss and neuropathological signs of AD. Inhibiting microglial ISR has opposite effects. Mechanistically, the authors show in vitro that ISR activation triggers the microglial secretion of neurotoxic lipids.

Jessica Waibl Polania and al.

In this study, the authors examined intratumoral cellular interactions governing the exhaustion of different T-cell subpopulations in a glioblastoma (GBM) murine model. Single-cell RNA-seq analyses revealed that the exhaustion of stem-like T-cells is more specifically associated with tumor progression. Tumor-associated macrophages (TAM) —rather than tumor cells— are the primary source of antigenic exposure driving the transition of exhausted stem-like T-cells to a terminally differentiated exhausted T-cell phenotype, which is less effective in mounting an antitumor response.

Linda Kachuri and al.

The authors conducted genetic analyses and complete blood count assessments in 3,418 glioma cases and 8,156 controls. They observed that a high platelet-to-lymphocyte ratio is associated with an increased risk of glioma, particularly in tumors harboring mutations in the gene encoding isocitrate dehydrogenase (IDH). Polygenic scores linked to certain blood phenotypic traits were also associated with various characteristics of the tumor immune microenvironment. These findings highlight novel mechanisms of immunogenetic susceptibility to glioma.

Jiancheng Gao and al.

The authors combined single-cell RNA-seq analysis with B-cell receptor (BCR) sequencing to study B-lineage cells infiltrating glioblastoma (GBM) tumors. The results reveal an enrichment of plasma cells that have undergone low levels of somatic hypermutation. The degree of plasma cell enrichment is associated with poor prognosis. Furthermore, the authors report that plasma cells secrete immunoglobulin G (IgG), which stimulates the proliferation of glioma stem cells through the IgG-FcγRIIA-AKT-mTOR axis.

Nicholas A. Vitanza and al.

The BrainChild-03 clinical trial is a phase 1, single-center, dose-escalation study testing repeated intracerebroventricular administration of CAR T-cells targeting the immune checkpoint molecule B7-H3 in children with recurrent diffuse intrinsic pontine glioma (DIPG). This trial demonstrates that the protocol is well tolerated, even with repeated doses over several years, and suggests potential clinical efficacy warranting further investigation in a multicenter phase 2 trial.