Ontology highlight
ABSTRACT:
PROVIDER: PRJNA572597 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10152091.fastq.gz | Fastqsanger.gz | |||
| SRR10152092.fastq.gz | Fastqsanger.gz | |||
| SRR10152093.fastq.gz | Fastqsanger.gz | |||
| SRR10152094.fastq.gz | Fastqsanger.gz | |||
| SRR10152095.fastq.gz | Fastqsanger.gz |
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Project description:T cells are often weakly responsive to tumor self-antigens because of central tolerance, which constrains their ability to eliminate tumors. Affinity-matured T cell receptors can exhibit enhanced tumor killing properties but in therapeutic settings have been accompanied by off-target cross-reactivity and toxicity, because high-affinity TCRs antigen specificity is altered compared to naturally selected TCRs. Here, we exploited the physiological biophysical mechanism of TCR activation through mechanical force, by engineering to a weakly reactive TCR specific for a non-mutated human prostate tumor associated antigen (TAA), Prostatic Acid Phosphatase (PAP). We isolated a catch bonding “hotspot” whose mutation enhanced T cell activity by increasing TCR-pMHC bond lifetime, whilst maintaining physiological affinities and antigen fine-specificities. T cells expressing these engineered TCRs showed vastly superior expansion and tumor killing properties in vitro and in vivo, as well as enhanced effector phenotypes and proliferation in the tumor, as measured by single-cell RNA-seq. High resolution structures and molecular dynamics simulations of the TCR-pMHC complexes reveal the structural hotspot in TCR CDR1 is primed for peptide interaction in the catch bond engineered TCR. These studies establish catch bond engineering as a viable biophysically-based strategy to convert tolerized anti-tumor T cells into potent TCR-T killers.
2026-03-25 | GSE307528 | GEO
Project description:T cells are often weakly responsive to tumor self-antigens because of central tolerance, which constrains their ability to eliminate tumors. Affinity-matured T cell receptors can exhibit enhanced tumor killing properties but in therapeutic settings have been accompanied by off-target cross-reactivity and toxicity, because high-affinity TCRs antigen specificity is altered compared to naturally selected TCRs. Here, we exploited the physiological biophysical mechanism of TCR activation through mechanical force, by engineering to a weakly reactive TCR specific for a non-mutated human prostate tumor associated antigen (TAA), Prostatic Acid Phosphatase (PAP). We isolated a catch bonding “hotspot” whose mutation enhanced T cell activity by increasing TCR-pMHC bond lifetime, whilst maintaining physiological affinities and antigen fine-specificities. T cells expressing these engineered TCRs showed vastly superior expansion and tumor killing properties in vitro and in vivo, as well as enhanced effector phenotypes and proliferation in the tumor, as measured by single-cell RNA-seq. High resolution structures and molecular dynamics simulations of the TCR-pMHC complexes reveal the structural hotspot in TCR CDR1 is primed for peptide interaction in the catch bond engineered TCR. These studies establish catch bond engineering as a viable biophysically-based strategy to convert tolerized anti-tumor T cells into potent TCR-T killers.
2026-03-25 | GSE307565 | GEO
Project description:The mitogen activated kinases ERK1/2 are activated by antigen receptor engagement and control T cell differentiation. We have used mass spectrometry to explore how ERK1/2 control antigen receptor driven cell growth and proteome restructuring in CD8 T cells. Quantitative analysis of >8000 proteins provides new understanding of the highly selective role of ERK1/2 in controlling T cell protein systems. The data reveal that ERK signalling is not a dominant regulator of the metabolic and biosynthetic programs that drive T cell growth. Rather, the dominant function of ERK1/2 is to control the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. This study provides a comprehensive map of how T cell phenotypes are selectively shaped by ERK1/2 and reveals that ERK1/2 controls the transcriptional reprogramming of activated T cells that is pivotal for T cell differentiation and acquisition of effector function.
2020-12-23 | PXD023256 | Pride
Project description:<p>Small cell lung cancer (SCLC) exhibits profound immunometabolic suppression that impairs antigen presentation and constrains immunotherapy efficacy. Through integrated multi-omics analyses of primary human SCLC tumors, we identified midkine (MDK) as a dominant tumor-secreted driver of immune evasion. Mechanistically, MDK activates STAT3 to induce indoleamine 2,3-dioxygenase 1 (IDO1), driving tryptophan-kynurenine metabolic reprogramming. This axis suppresses myeloid antigen presentation, reduces HLA class I expression, and impairs CD8+ T cell function, establishing a immunosuppressive tumor microenvironment (TME). We engineered DLL3-targeted CAR T cells secreting anti-MDK scFv. These dual-functional CAR T cells neutralize MDK within the TME, restore antigen presentation, alleviate metabolic suppression, and reinvigorate CD8+ T cell responses. In SCLC models, they exhibited markedly enhanced antitumor activity, improved metabolic fitness, and durable immune activation without systemic toxicity. Collectively, our findings identify MDK as a key immunometabolic regulator and support sMDK-DLL3 CAR T cells as a targeted immunotherapy for SCLC.</p>
2026-03-23 | MTBLS14116 | MetaboLights
Project description:Antibodies are central to the immune response against microbes. We have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the M protein of Streptococcus pyogenes. Here, we engineered Ab25 into the IgG2-4 subclasses. Despite reduced binding, the IgG3 version demonstrated enhanced opsonic function. Molecular dynamics (MD) simulations showed that IgG3s Fc exhibits extensive mobility in 3D space relative to the antigen due to its extended hinge region. The MD simulations also showed altered Fab-antigen interactions, in line with IgG3s diminished affinity. We explored the impact of hinge-engineering by generating a panel of IgG antibodies, IgGhxx, containing the CH1-3 domains of IgG1 and different segments of IgG3s hinge. Hinge-engineering enhanced opsonic function, with the most potent hinge having 47 amino acids. IgGh47 exceeded the parent IgG1 and, in some instances, the IgG3 version. The IgGh47 was protective against Streptococcus pyogenes in a systemic infection mouse model, contrary to parent IgG3 and IgG1. The in vitro phenotype of IgGh47 was generalizable to clinical isolates with different emm types. Finally, we generated IgGh47 versions of anti-SARS-CoV-2 mAbs, which exhibited strongly enhanced in vitro opsonic function compared to the original IgG1s. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function and how to enhance it for opsonic function.
2024-03-10 | MSV000094287 | MassIVE
Project description:The potency of regulatory T cell (Treg) therapy has been transformed through use of chimeric antigen receptors (CAR). However, to date, CAR Treg therapy has not achieved long-lasting tolerance in mouse models, suggesting that additional engineering is required to unlock the full potential of these cells. We previously found that human Tregs produce minimal amounts of IL-10 and have a limited capacity to control innate immunity in comparison to type I regulatory (Tr1) cells. Seeking to create “hybrid” CAR Tregs that were engineered with Tr1-like properties, we examined whether the PDCD1 locus could be exploited to endow Tregs with the ability to secrete high levels of IL-10 in a CAR-regulated manner.
2025-05-06 | GSE287328 | GEO
Project description:<p>Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-specific CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly among different individuals. A genetic influence was seen for the sharing of individual TCR sequences from antigen-specific cells, but not for repertoire richness or the selection of clonal dominance. VZV vaccination favored the expansion of infrequent VZV-specific TCRs including those from naïve T cells while leaving dominant T cell clones mostly unaffected.</p>
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Project description:Here we provide a framework to qualtitatively evaluate the tyrosine phosphorylation-mediated signaling pathways triggered by antigen-independent antibody and antigen-specific OVA peptide-MHC using Jurkat T cells expressing OT-1 T cell receptors. Our data suggest that pTyr-mediated regulatory axis triggered by OVA antigen-specific activation of TCR closely resembled that of antigen-independent stimulation using anti-TCR antibody, albeit OVA could likely induce a relatively stronger signaling effect. While data from this study do not invalidate previous studies of T cell signaling using antibody-based stimulation, our data revealed potential advantages of using peptide-MHC tetramers in studying T cell signaling. Antigen-specific activation of the OT-1 TCR using a panel of peptide-MHC tetramers (OVA, T4 and G4) generated data that correlates well with the corresponding binding affinity of the peptide-MHC, consistent with predicted signaling strength. Importantly, the apparent correlation between signaling strength and peptide-MHC affinity enables us to fine-tune the signaling strength of T cell stimulation in future studies, allowing a more precise control of the experimental parameter instead of a more binary antibody-based activation. Overall, we demonstrate the utility of BOOST to reveal new biological insights in the immune system.
2021-04-27 | PXD024579 | Pride
Project description:Myeloid-derived cells comprising the tumor stroma represent a heterogeneous population of cells critical to the structure, function and growth of established cancers. We have recently found that engineering tumor-specific CD8+ T cells to secrete IL-12 (IL-12TD) can lead to striking improvements in T-cell activity against established melanomas in murine models. Surprisingly, IL-12-dependent enhancement of CD8+ T-cell anti-tumor function did not occur through direct ligation of receptors on lymphocytes or NK cells. Instead, IL-12 sensitized host bone marrow-derived tumor-stromal cells, partly through interferon-gamma, to indirectly enhance the effects of adoptively-transferred T cells. Direct presentation of antigen by tumor was not necessary, but MHC class I expression on endogenous cells was essential for IL-12 mediated anti-tumor enhancements. Upon successful treatment with IL-12TD cells, we observed the selective elimination of tumor-infiltrating CD11b+ F4/80+ macrophages, CD11b+/ClassII+/CD11c+ dendritic cells and CD11b+/Ly6C+/Ly6G- but not CD11b+/Ly6C+/Ly6G+ myeloid-derived suppressor cells within regressing lesions. These results are consistent with a model whereby IL-12 triggers the maturation of myeloid-derived cells into competent antigen cross-presenting cells. Licensed recognition of these antigens by effector T cells may in turn trigger the collapse of the tumor stroma and aid in the regression of large vascularized lesions. Samples were collected at 3 days and 7 days from tumors treated in-vivo with no treatment, Mock pmel-1 CD8+ cell treatment, or IL-12 pmel-1 CD8+ cell treatment. There were 4 biological replicates of each sample type. There were a total of 24 samples.
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2023-08-18 | MSV000092691 | MassIVE