immunocompetent murine glioblastoma stem-like cell models exhibiting distinct phenotypes DOI Creative Commons
Kimia Kardani,

Shanawaz M. Ghouse,

Muzammil Arif Din Abdul Jabbar

et al.

Neuro-Oncology Advances, Journal Year: 2024, Volume and Issue: 7(1)

Published: Dec. 7, 2024

Glioblastoma (GBM) treatment is hindered by a dearth of representative mouse GBM preclinical models in immunocompetent mice. Here, we characterized 5 murine stem-like cell (mGSC) derived from lentivirus-induced tumors transgenic mice that are driven the activation Nf1-Ras signaling pathway and inactivation Tp53. MGSC lines (005, RIG, NF53, C1, C3) were cultured as spheres serum-free stem media. Whole exome sequencing (WES) was employed to quantify single nucleotide polymorphisms (SNPs). Stem properties stemness vitro tumorigenicity after intracerebral implantation C57BL/6 Tumor phenotypes immune microenvironment immunohistochemistry, flow cytometry, RNA sequencing. WES revealed large variation coding sequence SNPs across mGSC (~20-fold), likely influenced mixed backgrounds parental MGSCs exhibited variable clonogenic sphere formation CD133 expression levels. In vivo, they consistently initiated lethal malignant gliomas, with median survival ranging 29 82 days, showed strong CD44 invasiveness. The tumor featured an abundance CD68+ macrophages uniform high PD-L1+ myeloid cells, while T-cell infiltration varied among models, low mutation burden C1 C3 exhibiting fewer tumor-infiltrating T cells. Upon orthotopic mice, mGSCs generate characteristic human GBM. Despite similar strategies these mGSCs, range profiles mGSC-derived tumors. These provide new for developing immunotherapies.

Language: Английский

GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases DOI Creative Commons
Feng Lan, Jizhou Li,

Wenxuan Miao

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Inflammatory diseases are often chronic and recurrent, current treatments do not typically remove underlying disease drivers1. T cells participate in a wide range of inflammatory such as psoriasis2, Crohn's disease3, oesophagitis4 multiple sclerosis5,6, clonally expanded antigen-specific may contribute to chronicity recurrence, part by forming persistent pathogenic memory. Chronic rhinosinusitis asthma airway that present comorbidities7. affects more than 10% the general population8. Among these patients, 20–25% would develop nasal polyps, which require repeated surgical resections owing high incidence recurrence9. Whereas abundant infiltrate polyps tissue10,11, cell subsets drive pathology promote recurrence fully understood. By comparing repertoires polyp tissues obtained from consecutive surgeries, here we report CD8+ clones carrying effector memory-like features colonize mucosal tissue during characteristically express tryptase Granzyme K (GZMK). We find GZMK cleaves many complement components, including C2, C3, C4 C5, collectively activation cascade. GZMK-expressing organized tertiary lymphoid structures, levels predict severity comorbidities better well-established biomarkers eosinophilia interleukin-5. Using mouse model, further show exacerbate manner dependent on proteolytic activity complements. Genetic ablation or pharmacological inhibition after onset markedly alleviates restores lung function. Our work identifies memory subset promotes inflammation recurrent molecule suggests potential therapeutic target. Comparing surgeries shows producing K, complement-activating tryptase, is

Language: Английский

Citations

5
CD8+ T cell exhaustion in the tumor microenvironment of breast cancer DOI Creative Commons

Hanghang Xie,

Xiaowei Xi, Ting Lei

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 9, 2024

CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as cell exhaustion (TEX). The aim checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood. This review defines TEX and outlines features underlying mechanisms. It also discusses primary mechanisms cancer, covering inhibitory receptors, immunosuppressive cells, cytokines, transcriptomic epigenetic alterations, metabolic reprogramming, exosome pathways, offering insights into potential immunotherapy strategies for cancer.

Language: Английский

Citations

14
T cell exhaustion and senescence for ovarian cancer immunotherapy DOI
Jiao Zhao,

Zhongmiao Wang,

Yingying Tian

et al.

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 104-105, P. 1 - 15

Published: July 18, 2024

Language: Английский

Citations

9
Co-evolution of glioma and immune microenvironment DOI Creative Commons
Mahmoud Elguindy, Jacob S. Young, Winson S. Ho

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(12), P. e009175 - e009175

Published: Dec. 1, 2024

Glioma evolution is governed by a multitude of dynamic interactions between tumor cells and heterogenous neighboring, non-cancerous cells. This complex ecosystem, termed the microenvironment (TME), includes diverse immune cell types that have gained increasing attention for their critical paradoxical roles in control tumorigenesis. Recent work has revealed cellular composition functional state TME can evolve extensively depending on stage intrinsic features surrounding glioma Concurrently, adaptations to phenotype, including activation various states, occur context these alterations. In this review, we summarize important play key during each progression, from initiation escape, invasion recurrence. Understanding interplay development effective immunotherapies treatment.

Language: Английский

Citations

4
Spatial omics shed light on the tumour organisation of glioblastoma DOI Creative Commons
James R. Whittle, Jurgen Kriel, Ebenezer O. Fatunla

et al.

Seminars in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 167, P. 1 - 9

Published: Jan. 8, 2025

Language: Английский

Citations

0
A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types DOI Creative Commons
Zhen Zeng,

Tianbei Zhang,

Jiajia Zhang

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 3, 2025

Abstract Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 ( ENTPD1 ), low IL-7 receptor IL7R ) in many cancer types, but their collective relevance functionality has not established. Here we present an integrative tool identify MANA-specific TIL using weighted expression these three genes lung melanoma single-cell RNAseq datasets. Our three-gene “MANAscore” algorithm outperforms other RNAseq-based algorithms identifying validated neoantigen-specific clones, accurately identifies TILs recognize classes tumor antigens, including testis endogenous retroviruses viral oncogenes. Most are characterized by a tissue resident memory gene program. Putative tumor-reactive cells (pTRC) identified via MANAscore anti-PD-1-treated tumors had higher checkpoint cytotoxicity-related relative putative non-tumor-reactive cells. pTRC pathologically responding showed distinguished patterns trajectories. Collectively, show is robust can greatly enrich candidate be used understand the functional programming TIL.

Language: Английский

Citations

0
The conundrum of CD8+ T cell trajectories in low antigenic tumors: How to overcome a hypofunctional state distinct from antigen-driven exhaustion? DOI Creative Commons
Angeliki Datsi,

Rüdiger V. Sorg,

Abhishek D. Garg

et al.

Genes and Immunity, Journal Year: 2024, Volume and Issue: 25(5), P. 353 - 355

Published: Oct. 9, 2024

Language: Английский

Citations

1
immunocompetent murine glioblastoma stem-like cell models exhibiting distinct phenotypes DOI Creative Commons
Kimia Kardani,

Shanawaz M. Ghouse,

Muzammil Arif Din Abdul Jabbar

et al.

Neuro-Oncology Advances, Journal Year: 2024, Volume and Issue: 7(1)

Published: Dec. 7, 2024

Glioblastoma (GBM) treatment is hindered by a dearth of representative mouse GBM preclinical models in immunocompetent mice. Here, we characterized 5 murine stem-like cell (mGSC) derived from lentivirus-induced tumors transgenic mice that are driven the activation Nf1-Ras signaling pathway and inactivation Tp53. MGSC lines (005, RIG, NF53, C1, C3) were cultured as spheres serum-free stem media. Whole exome sequencing (WES) was employed to quantify single nucleotide polymorphisms (SNPs). Stem properties stemness vitro tumorigenicity after intracerebral implantation C57BL/6 Tumor phenotypes immune microenvironment immunohistochemistry, flow cytometry, RNA sequencing. WES revealed large variation coding sequence SNPs across mGSC (~20-fold), likely influenced mixed backgrounds parental MGSCs exhibited variable clonogenic sphere formation CD133 expression levels. In vivo, they consistently initiated lethal malignant gliomas, with median survival ranging 29 82 days, showed strong CD44 invasiveness. The tumor featured an abundance CD68+ macrophages uniform high PD-L1+ myeloid cells, while T-cell infiltration varied among models, low mutation burden C1 C3 exhibiting fewer tumor-infiltrating T cells. Upon orthotopic mice, mGSCs generate characteristic human GBM. Despite similar strategies these mGSCs, range profiles mGSC-derived tumors. These provide new for developing immunotherapies.

Language: Английский

Citations

0