Localized PD-1 CAR T therapy reprograms neuroinflammation - human CSF data.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE308973 | GEO | 2026/07/21
REPOSITORIES: GEO
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Project description:B cell-depleting therapies are effective in multiple sclerosis (MS), yet many patients continue to accumulate disability, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA-seq atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched IgG⁺ B cells and plasma cells in the CSF of patients with MS. Unbiased analysis further identified a rare subset of activated, TCR-restricted, PD-1⁺ T follicular helper-like cells with B-cell recruiting features that was enriched in the CSF of patients with MS. To target this population therapeutically, we developed PD-1-directed CAR T cells that selectively depleted pathogenic PD-1⁺ CD4 T cells and, in armored versions, released IL-10 at inflammatory sites. This strategy attenuated CNS inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. Together, these findings define a cellular framework for CNS-localized adaptive immunity in MS and nominate a selective strategy to disrupt it.
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2025-06-25 | GSE300750 | GEO
Project description:Background: Adoptive cell therapy (ACT) with genetically engineered T cells expressing chimeric antigen receptors (CARs) has emerged as a promising treatment option for refractory leukaemia or lymphoma patients. Despite its success in type B malignancies, CAR-T cell therapy still faces challenges such as toxicity, inactivation by the tumour microenvironment (TME), and low cell persistence in patients. Results: In this study, we developed an AAV6/Cas9-based knock-in platform to repurpose the PD-1 locus for inducible IL-15 expression. We initially demonstrated that anti-CD19 CAR-T cells lacking PD-1 expression exhibited reduced expansion capacity and overall fitness compared to control CAR-T cells. However, as expected, they showed an improved ability to lyse PDL1+ target cells compared to CAR-T WT cells. To enhance the fitness of PD-1 KO CAR-T cells, we generated PD-1KIL-15 CAR-T cells, which, in addition of been PD-1 KO, express IL-15 under the control of the PD-1 endogenous promoter. Compared to CAR T PD-1 KO cells, PD-1KIL-15 CAR-T cells I displayed improved phenotype, viability and metabolism... More importantly, they also demonstrated enhanced lytic capacity of PDL1+ CD19+ target cells, correlating with increased resistance to apoptosis and improved cell fitness. Conclusions: In summary, we present a new gene editing platform to generate 4th generation CAR-T cells (TRUCKs) that are PD-1 KO and express IL-15 upon T cell activation and/or exhaustion. This platform addresses the limitations associated with knocking-out PD-1 and those associated with sustained IL-15 cytokine expression. The same platform can be used to generate PD-1 KO TRUCKs targeting different antigens and expressing different cytokines under the control of the PD-1 gene promoter.
2026-07-02 | GSE337294 | GEO
Project description:Elevated frequencies of GM-CSF-producing helper T (TH) cells are consistently found in multiple sclerosis (MS) patients and GM-CSF expression is a non-redundant feature of pathogenic TH cells in preclinical models of MS. GM-CSF activates an inflammatory signature in monocytes, and their progeny are the most abundant cellular infiltrate in acute MS lesions. To model deregulated GM-CSF levels, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral TH cells. This antigen-independent GM-CSF release induced severe neurological deficits with almost 100% penetrance, accompanied by the infiltration of inflammatory monocyte-derived myeloid cells into the brain stem and spinal cord. Other organs did not show obvious signs for clinical pathology, despite also being infiltrated by inflammatory myeloid cells. We aim to unravel differences between organs, their responses by sequencing CD45-negative tissue cells isolate from the CNS and the lung.
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Project description:Background: Multiple sclerosis is a neurodegenerative autoimmune disorder of the central nervous system (CNS) in which autoreactive immune cells migrate through a damaged blood brain barrier, resulting in focal demyelinating lesions of both the white and grey matter. Of increasing interest is the repeated observation that beyond focal lesions, there are also diffuse, surface-in gradients of pathology in MS, wherein damage is most severe directly adjacent to cerebrospinal fluid (CSF)-contacting surfaces, such as the subpial and periventricular areas. This observation suggests that toxic factors within MS CSF may be contributing to the emer-gence and/or evolution of surface-in gradients. Directly separating the CSF from the periventricular parenchyma are ependymal cells – a glial epithelium that expresses tufts of motile cilia which are critical for circulating CSF solutes and regulating local fluid flow. While damage to ependymal cilia has the potential to drastically modify CSF homeostasis and thus contribute to the damage of CSF exposed regions, these motile cellular structures have yet to be investigated in the context of MS. Methods: We first conducted single cell RNA sequencing of fresh human periventricular brain tissue containing ependymal cells from MS patients and non-MS disease controls. We subse-quently collected CSF from MS patients and exposed cultured rodent ependymal cells to this CSF in order to evaluate impact on ependymal ciliary function. To complement our direct eval-uation of cilia in the context of MS, we also confirmed whether cilia were altered in a classic animal model of MS, experimental autoimmune encephalomyelitis (EAE), and also designed a novel transgenic animal model to evaluate the cellular and behavioural effect(s) of adult ep-endymal ciliary disruption. Results: Single cell RNA sequencing analysis of human ependymal cells in MS demonstrated largescale dysregulation of ciliary genes; in situ stains of MS brain tissue confirmed a loss of ependymal cilia in MS compared to control. Exposure of ependymal cells to MS CSF led to transcriptional modification of ciliary gene expression and reduced ciliary beating frequency. Likewise, analysis of ependymal cells in EAE also demonstrated altered cilia gene expression. Conditional knockout of the critical cilia-associated gene Ccdc39 in ependymal cells led to transient ventricular enlargement, increased periventricular microglial density, and alterations in nesting behaviour. Conclusion: These data suggest that cilia are dysregulated in CNS autoimmunity. More im-portantly, however, they provide evidence to suggest that ependymal cilia disruption could play an active role in the development of periventricular pathology in MS, and can lead to behav-ioural deficits that may underlie aspects non-motor MS symptomatology.
2025-12-31 | GSE301585 | GEO
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2026-01-06 | GSE301791 | GEO
Project description:CAR-T cell therapy is effective in hematologic malignancies but not in solid tumors. In breast and lung cancer patients, CAR-T cells targeting ROR1 infiltrated tumors poorly and became dysfunctional. To test strategies for enhancing efficacy, we induced ROR1+ lung tumors in KrasLSL-G12D/+;p53fl/f mice. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently controlled tumor growth but infiltrated tumors poorly and lost function, as observed in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activated tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improved CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.
2020-09-18 | GSE158110 | GEO