Cerebral malaria (CM) is a severe encephalopathy caused by Plasmodium parasite infection, resulting in thousands of annual deaths and neuro-cognitive sequelae even after anti-malarial drugs treatment. Despite efforts to dissect the mechanism, the cellular transcriptomic reprogramming within the spatial context remains elusive. Here, we constructed single-cell and spatial transcriptome atlases of experimental CM (ECM) male murine brain tissues with or without artesunate (ART) treatment. We identified activated inflammatory endothelial cells during ECM, characterized by a disrupted blood-brain barrier, increased antigen presentation, and leukocyte adhesion. We also observed that inflammatory microglia enhance antigen presentation pathway such as MHC-I to CD8+ cytotoxic T cells. The latter underwent an inflammatory state transition with up-regulated cytokine expression and cytotoxic activity. Multi-omics analysis revealed that the activated interferon-gamma response of injured neurons during ECM and persisted after ART treatment. Overall, our research provides valuable resources for understanding malaria parasite-host interaction mechanisms and adjuvant therapy development.
© 2025. The Author(s).

Loss or downregulation of major histocompatibility complex class I (MHC-I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin-like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular mechanisms underlying ANGPTL2 tumor-promoting activity in the tRCC model remained unclear. Here, we report that ANGPTL2 deficiency in renal tubular epithelial cells slows tumor progression in the tRCC mouse model and promotes activated CD8+ T-cell infiltration of kidney tissues. We also found that Angptl2-deficient tumor cells show enhanced interferon γ-induced expression of MHC-I and increased susceptibility to CD8+ T-cell-mediated anti-tumor immune responses. Moreover, we provide evidence that the ANGPTL2-α5β1 integrin pathway accelerates polycomb repressive complex 2-mediated repression of MHC-I expression in tumor cells. These findings suggest that ANGPTL2 signaling in tumor cells contributes to tumor immune evasion and that suppressing that signaling in tumor cells could serve as a potential strategy to facilitate tumor elimination by T-cell-mediated anti-tumor immunity.
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.
© 2023. The Author(s).

The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.
To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.
We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.
Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.
These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffusive tumor-infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to tumor core was also found in human GBM. The levels of VEGF and VEGFR2 showed a spatial correlation with the extent of vascular abnormality spanning the tumor invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in invasion-associated vascular transition. As ANGPT2 was expressed only in a portion of the central tumor vessels, we developed a ligand-independent Tie2-activating antibody that can phosphorylate Tie2 in vivo . This agonistic Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo . Thus, our study reveals that the normal-to-tumor vascular transition spatio-temporally associates with GBM invasion and may be controlled by Tie2 activation with a novel mechanism-of-action.