01
T cell exhaustion is a significant obstacle in the field of cancer immunotherapy. In this study, the authors observed that the ratio of progenitor to terminal exhaustion of glioblastoma (GBM) infiltrated CD8+ T cells (progenitor exhaustion-to-terminal exhaustion ratio, PETER) went down over time. Such phenomenon made GBM a good model to study the transition from progenitor-exhausted T (Tex_prog) cells to terminally exhausted T (Tex_term) cells. The authors then performed single-cell RNA sequencing (scRNA-seq) to determine transcriptional heterogeneity among these cells. It was found that Tex_prog cells expressed effector and stem-like genes, while Tex_term cells highly expressed exhaustion-related and cytotoxic-related genes. The progression from progenitor cells through intermediate populations to terminal depletion was further confirmed by pseudotime analysis. Through cell-cell interaction analysis, tumor-associated macrophages (TAMs) were identified as the most abundant antigen-presenting cells (APCs) in intracranial tumor microenvironment (TME). Compared with other APCs, TAMs exhibited stronger phagocytosis and cross-presentation capabilities. In vitro co-culture experiments also supported the importance of TAM antigen presentation in driving T cell exhaustion. CellChat analysis further predicted secondary interactions between TAMs and CD8+ T cells in mice and humans that may contribute to exhaustion progression, including the pathways of intercellular adhesion, migration and stimulatory molecules. Finally, they confirmed that increasing PETER via TAM depletion led to improved αPD1 efficacy in checkpoint blockade-responsive models. These results highlighted TAM-T cell interactions and TAM antigen presentation as critical for driving CD8+ T cell exhaustion progression in GBM and other solid tumors.
DOI: 10.1016/j.immuni.2024.11.026
02
Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, was found to exhibit a reduced signature in the adipose tissues of individuals and mice with obesity. The underlying mechanisms remain largely unclear. In this paper, researchers demonstrated that reactivating ferroptotic signaling using agonists like RSL3, or through genetic approaches, including overexpression of Acsl4 and deletion of Fth, significantly reduced lipid accumulation in adipocytes and mitigated obesity in high-fat diet-fed mice. Mechanistically, they identified that ferroptotic signaling destabilized hypoxia-inducible factor 1-alpha (HIF1α) by promoting its degradation via the prolyl hydroxylase domain protein 2 (PHD2). This destabilization derepressed thermogenic pathways regulated by the c-Myc-PGC1β axis, enhancing mitochondrial activity and thermogenesis in adipose tissue, particularly in white adipose tissue that transitions into a beige state. Enhanced thermogenesis effectively counteracted adipose tissue expansion and reduced systemic metabolic dysfunction associated with obesity. Mouse models of adipocyte-specific Acsl4 overexpression and Fth deletion presented improvement of metabolic profiles, including enhanced insulin sensitivity and reduced serum lipid levels. These findings highlighted ferroptotic signaling as a critical regulator of adipose tissue plasticity and a promising therapeutic target for combating obesity and related metabolic diseases.
DOI: 10.1016/j.cmet.2024.11.010
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