Single-cell and spatial analyses reveal the effect of VSIG4+S100A10+TAMs on the immunosuppression of glioblastoma and anti-PD-1 immunotherapyLiu, Yang, Fang
et alInt J Biol Macromol (2025)
Abstract: Therapeutic strategies aiming at the tumor immune microenvironment (TIME) hold promise for glioblastoma (GBM) treatment. However, adjuvant immunotherapies targeting checkpoint inhibitors just prove effective for a selected group of GBM patients. The extensive involvement of GBM-associated macrophages highlights their potential role in tumor behavior. In-depth exploration of the impact of macrophages on the efficacy of immunotherapy is crucial for enhancing treatment outcomes. In this study, we conducted a comprehensive analysis using bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to explore the heterogeneity of tumor-associated macrophages (TAMs) in GBM. Flow cytometry was employed to investigate the effects of VSIG4 on TAM phenotypes, and co-culture cellular assays were performed to evaluate its contribution to GBM malignancy. Integrating 16 patient samples, we examined the immunological significance of VSIG4+S100A10+TAMs. VSIG4 expression on macrophages is significantly upregulated and correlated with the TIME, promoting the polarization of macrophages towards M2 and facilitating GBM progression. Spatial transcriptomics and human samples multiplex immunofluorescence (mIF) confirmed the co-localization of VSIG4+S100A10+TAMs with various T cells, resulting in the inhibition of T cell immune responses and a reduction in anti-tumor immunity. Our findings demonstrate for the first time that VSIG4+S100A10+TAM is an independent prognostic indicator of poor outcome for GBM and markedly accumulates in patients exhibiting non-responsiveness to anti-PD-1 immunotherapy. Targeting this specific bifunctional subgroup can potentially open up new avenues for the immunotherapy of GBM.Copyright © 2025. Published by Elsevier B.V.
Genomic Exploration of Essential Hypertension in African-Brazilian Quilombo Populations: A Comprehensive Approach With Pedigree Analysis and Family-Based Association StudiesBorges, Horimoto, Wijsman
et alJ Am Heart Assoc (2025)
Abstract: Essential hypertension (EH) is a global health issue. Despite extensive research, much of EH heritability remains unexplained. We investigated the genetic basis of EH in African-derived individuals from partially isolated quilombo populations in Vale do Ribeira (São Paulo, Brazil).Samples from 431 individuals (167 affected, 261 unaffected, 3 unknown) were genotyped using a 650 000 single-nucleotide polymorphism array. Estimated global ancestry proportions were 47% African, 36% European, and 16% Native American. We constructed 6 pedigrees using additional data from 673 individuals and created 3 nonoverlapping single-nucleotide polymorphism subpanels. We phased haplotypes and performed local ancestry analysis to account for admixture. Genome-wide linkage analysis and fine-mapping via family-based association studies were conducted, prioritizing EH-associated genes through a systematic approach involving databases like PubMed, ClinVar, and GWAS (Genome-Wide Association Studies) Catalog. Linkage analysis identified 22 regions of interest with logarithm of the odds scores ranging from 1.45 to 3.03, encompassing 2363 genes. Fine-mapping (family-based association studies) identified 60 EH-related candidate genes and 117 suggestive/significant variants. Among these, 14 genes, including PHGDH, S100A10, MFN2, and RYR2, were strongly related to hypertension harboring 29 suggestive/significant single-nucleotide polymorphisms.Through a complementary approach combining admixture-adjusted Genome-wide linkage analysis based on Markov chain Monte Carlo methods, family-based association studies on known and imputed data, and gene prioritizing, new loci, variants, and candidate genes were identified. These findings provide targets for future research, replication in other populations, facilitate personalized treatments, and improve public health toward African-derived underrepresented populations. Limitations include restricted single-nucleotide polymorphism coverage, self-reported pedigree data, and lack of available EH genomic studies on admixed populations for independent validation, despite the performed genetic correlation analyses using summary statistics.
Differential expression of S100A10 protein in leukocytes and its effects on monocyte emigration from bone marrowZhao, Jiang, Lv
et alJ Immunol (2025)
Abstract: Although the importance of the unique member of S100 EF-hand family, S100A10 in health and disease is well appreciated, a precise characterization of S100A10 expression still remains elusive. To this purpose, we generated a knock-in mouse line in which downstream of the coding sequence of the S100a10 gene was inserted IRES-mCherry-pA sequence. Interestingly, mCherry fluorescence was widely distributed in splenic myeloid and lymphoid cells, whereas neutrophils showed a negligible mCherry level. By taking advantage of these reporter mice, we found Ly6C+ monocytes expressed the highest levels of S100A10 and bound significantly more plasminogen compared with the other respective leukocyte subsets. Furthermore, we demonstrated that S100A10 was required for emigration of Ly6C+ monocytes from bone marrow by mainly affecting CCR2 cell surface presentation. S100a10-/- mice had fewer circulating Ly6C+ monocytes and, after challenged with thioglycolate, accumulated less CCR2+ monocytes in bone marrow. However, S100A10 was not necessary for efficient neutrophil recruitment from the blood to inflamed tissue. These findings provide evidence that S100A10 is critical for monocyte mobilization and suggest its differential regulatory roles for monocyte and neutrophil chemoattractants in leukocyte homeostasis. Thus, targeting the S100A10-CCR2 pathway may be an attractive approach to regulate inflammatory responses and infectious diseases.© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
SARS-CoV2 infection triggers inflammatory conditions and astrogliosis-related gene expression in long-term human cortical organoidsColinet, Chiver, Bonafina
et alStem Cells (2025)
Abstract: SARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons and inhibitory neurons in 6 months human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations that led to changes in their morphology and upregulation of SERPINA3, CD44 and S100A10 astrogliosis markers. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrogliosis and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and lead to resilience of dysregulated neurons and astrocytes within an inflammatory environment.© The Author(s) 2025. Published by Oxford University Press.
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