Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Patient-Derived Lymphoma Spheroids Reveal Predictive Markers of Glofitamab Resistance in Relapsed/Refractory B-NHL

ABSTRACT: Bispecific antibodies (bsAbs) such as glofitamab represent a promising therapeutic approach for relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL), but resistance mechanisms remain poorly understood. This study aimed to identify predictive markers of bsAbs resistance based on the response of 3D patient-derived lymphoma spheroids (PDLS) established from R/R B-NHL samples. PDLS were treated with 0.1 nM glofitamab for 3 days and B-cell depletion was quantified as measure of ex vivo treatment response. Comprehensive immune profiling were performed on patient samples using multiparametric flow cytometry, single-cell RNA sequencing, CODEX spatial proteomics and functional assays. This study revealed that high responders to glofitamab possessed more activated CD8+ T-cells with higher cytotoxic signatures, while low responders showed enriched exhausted CD8+ T-cell populations with enhanced expression of exhaustion markers (TIGIT, LAG3, PD1). Moreover, low responders demonstrated elevated functional CD4+ T-follicular helper (Tfh) cells in close proximity to malignant B-cell thus promoting their survival through IL21 and CXCL13 signaling pathways. Functional experiments have shown that adding anti-TIGIT co-treatment enhanced glofitamab efficacy in low responder samples, and Tfh depletion improved cytotoxic T-cell function. Our findings identify CD8+ T-cell exhaustion and functionally activated Tfh cells as key resistance mechanisms to glofitamab in R/R B-NHL. Targeting these pathways represents a promising strategy to overcome bsAb resistance and improving therapeutic outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306092 | GEO | 2026/04/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Defining memory-like CD8 T cells that respond to PD-1 therapy in chronic viral infection

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naÃ¯ve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naÃ¯ve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed

2016-08-02 | E-GEOD-84105 | biostudies-arrayexpress

Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine

Project description:Background Follicular lymphoma (FL), the most common indolent non-Hodgkin’s Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses. Methods To capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability. Results FL-PDLS, mainly composed of tumor B cells (60% on average) and autologous T cells (13% CD4 and 3% CD8 on average, respectively), rapidly organizes into patient-specific three-dimensional (3D) structures of three different morphotypes according to 3D imaging analysis. RNAseq analysis indicates that FL-PDLS reproduces FL hallmarks with the overexpression of cell cycle, BCR, or mTOR signaling related gene sets. FL-PDLS also recapitulates the exhausted immune phenotype typical of FL-LN, including expression of BTLA, TIGIT, PD-1, TIM-3, CD39 and CD73 on CD3+ T cells. These features render FL-PDLS an amenable system for immunotherapy testing. With this aim, we demonstrate that the combination of obinutuzumab (anti-CD20) and nivolumab (anti-PD1) reduces tumor load in a significant proportion of FL-PDLS. Interestingly, B cell depletion inversely correlates with the percentage of CD8+ cells positive for PD-1 and TIM-3. Conclusions In summary, FL-PDLS is a robust patient-derived 3D system that can be used as a tool to mimic FL pathology and to test novel immunotherapeutic approaches in a context of personalized medicine.

2024-02-28 | GSE256457 | GEO

TIGIT expression on CD8+ T cells correlates with higher cytotoxic capacity

Project description:Persistent exposure to antigen leads to T cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers TIGIT and PD-1 in HIV-infected and healthy individuals and the relationship with cytotoxic CD8+ T lymphocyte (CTL) activity. Frequencies of TIGIT but not PD-1 positively correlated with CTL activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed upregulation of genes associated with antiviral immunity in TIGIT+ versus TIGIT-CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.

2021-03-31 | GSE171172 | GEO

Sequential single-cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-HodgkinÃ¢Â€Â™s lymphoma

Project description:Employed single cell RNA sequencing and protein surface marker profiling of serialCAR-T cell samples from patients with non-HodgkinÃ¢Â€Â™s lymphoma (NHL) to reveal CAR-T cell evolution, identify biomarkers of response, and test for evidence of exhaustion inCAR-T cells of poor responders. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly-differentiated, andexhausted state that is enriched in CAR-T cells of patients with poor response.Furthermore, we identified the checkpoint receptor TIGIT as a novel prognosticbiomarker and potential driver of CAR-T cell exhaustion.

| EGAS00001005356 | EGA

All -trans retinoic acid suppresses CD8+ T cell terminal exhaustion which enhances anti–PD-1 efficacy against glioblastoma [RNA-Seq]

Project description:Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade (ICB), particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. Therefore, better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and thereby improve the efficacy of immunotherapy. In this study, we find that all-trans retinoic acid (ATRA) suppresses CD8⁺ T cell terminal exhaustion. Administration of ATRA during CD8⁺ T cell activation in vitro conferred resistance to terminal exhaustion and preserved effector cytokine production and effector function. Mechanistically, ATRA selectively induced the expression of the long isoform of T cell factor 1 (TCF-1βBD), through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8⁺ T cells exhibited exhaustion resistance, which led to superior tumor-infiltrating CD8+ T cell polyfunctionality and enhanced glioma suppression. Oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8+ T cells and synergized with anti-PD-1 therapy, overcoming resistance in mouse models of glioma. Synergistic ATRA administration and anti-PD-1 treatment displayed significant therapeutic potential in mouse recurrent glioma model. Single-cell transcriptomic analysis of glioblastoma patients receiving anti-PD-1 therapy revealed that CD8⁺ T cells from responders were enriched for retinoic acid responsive and WNT-associated gene signatures, which correlated with improved survival. These findings establish ATRA as a modulator of CD8⁺ T cell exhaustion by inducing WNT/β-catenin dependent TCF-1βBD expression. This pathway offers therapeutic potential to overcome resistance to ICB in glioma.

2026-05-21 | GSE320177 | GEO

Single-cell Transcriptomics Reveal Signatures of Altered B cell Response and T cell Senescence in Geriatric Non-responders to COVID-19 mRNA Vaccination

Project description:The immune response to COVID-19 vaccines is diminished in older individuals. To understand the underlying immunobiology, we analyzed single-cell RNA-seq data from PBMCs of SARS-CoV-2 naïve nursing home residents with varying humoral responses following BNT162b2 vaccination and validated via flow cytometry. Responders (>4500 AU/mL anti-spike titers) showed enrichment for naïve B cell (IGHD, BACH2, CD22) and naïve CD4 T cell and early Tfh-related genes (CCR7, TCF7, LEF1, IL6ST, TGFBR2). Non-responders (<20 AU/mL) displayed elevated markers of T cell senescence (KLRG1, CCL4, CCL5, IL32), immune exhaustion (PD-1), and inflammation (TNF-α, IFN-γ). Flow cytometry revealed reduced CD4 T and B cell frequencies but higher CD8 T and NK cells in non-responders. Despite reduced B cell frequency, non-responders upregulated plasma B cell genes (PRDM1, XPB1, IRF4), suggesting dysregulated B cell differentiation. Our findings point to impaired lymphocyte responses and increased immunosenescence in non-responders, emphasizing the need for enhanced vaccine strategies in aging populations.

2026-03-20 | GSE300265 | GEO

Exploration of transcriptomic and proteomic profiles of the tumor microenvironment of marginal zone lymphoma

Project description:The role of the tumor microenvironment (TME) and intratumoral T cells in splenic marginal zone lymphoma (sMZL) is largely unknown. In the present study, we evaluated 36 sMZL spleen specimens by single cell analysis to gain a better understanding of the TME in sMZL. Using mass cytometry (CyTOF), we observed that the TME in sMZL is distinct from that of control non-malignant reactive spleen (rSP). We found that the number of TFH cells varied greatly in sMZL, ICOS+ TFH cells were more abundant in sMZL than rSP, and TFH cells positively correlated with increased numbers of memory B cells. Treg cell analysis revealed that TIGIT+ Treg cells are enriched in sMZL and correlate with suppression of TH17 and TH22 cells. Intratumoral CD8+ T cells were comprised of subsets of short-lived, exhausted and late-stage differentiated cells, thereby functionally impaired. We observed that T-cell exhaustion was present in sMZL and TIM-3 expression on PD-1low cells identified cells with severe immune dysfunction. Gene expression profiling by CITE-seq analysis validated this finding. Taken together, our data suggest that the TME as a whole, and T-cell population specifically, are heterogenous in sMZL and immune exhaustion is one of the major factors impairing T-cell function.

2025-01-15 | GSE286927 | GEO

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy.

2023-03-18 | GSE227399 | GEO

Defining memory-like CD8 T cells that respond to PD-1 therapy in chronic viral infection

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy.

2016-08-02 | GSE84105 | GEO

The IFN-I-DUSP2-NFAT axis Limits Tumor Remodeling and Immunotherapy Response in Lung Cancer

Project description:Type I interferons (IFN-I) exert context-dependent effects in tumor microenvironment (TME), but their role in shaping immunotherapy response remains unclear. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after immune checkpoint blockade (ICB), stratified by treatment outcome. In responders, ICB induced B cell and T follicular helper (Tfh) cell expansion, promoting the formation of tertiary lymphoid structure (TLS)-like niche. By contrast, non-responders exhibited sustained IFN-I signaling and accumulation of CD36⁺ SPP1⁺ tumor-associated macrophages (TAMs), which secreted IFN-I and disrupted lymphoid aggregation. At baseline, aberrant NFAT signaling in T cells marked a dysfunctional state. Mechanistically, IFN-I upregulated the phosphatase DUSP2 in pre-exhausted T cells, which dephosphorylated NFAT and promoted its nuclear localization. Nuclear NFAT transactivated genes encoding inhibitory receptors to reinforce T cell exhaustion. Deletion of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, improving response to PD-1 blockade. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that constrains immunotherapy efficacy in LUSC.

2025-07-19 | GSE302517 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data