Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CX3CR1⁺ CD8⁺ Cytotoxic T Cells Drive Tumor Killing in Esophageal Squamous Cell Carcinoma During Neoadjuvant Therapy

ABSTRACT: The efficacy of immune checkpoint blockade (ICB) in esophageal squamous cell carcinoma (ESCC) remains highly variable, and the underlying mechanisms driving differential responses are poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq), T cell receptor (TCR) sequencing, and whole exome sequencing (WES) on 52 ESCC patients from a phase III neoadjuvant clinical trial to characterize the tumor microenvironment (TME) and its association with therapeutic outcomes. We identified a selective expansion of non-exhausted cytotoxic CD8⁺ T cells, particularly CX3CR1⁺ CD8⁺ T cells, in well responders, driven by the CX3CL1-CX3CR1 axis. These cells exhibited high cytotoxicity, clonal expansion, and tumor-killing potential, while exhausted T cell subsets, including CXCL13⁺ CD8⁺ T cells, were reduced in well responders. Pre-treatment tumor mutational profiles revealed that a high cancer cell fraction (CCF) mutation burden and neoantigen abundance were predictive of response, with immune editing reducing immunogenic mutations post-treatment. Additionally, tumor epithelial differentiation (Gp1/Gp2 subtypes) and stromal remodeling influenced treatment outcomes, with Gp2 tumors associated with immune suppression and resistance. Our findings provide new insights into the immune dynamics of ESCC, highlighting CX3CR1⁺ CD8⁺ T cells, the CX3CL1-CX3CR1 axis, and tumor differentiation as potential therapeutic targets to enhance ICB efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314906 | GEO | 2026/08/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Intratumoral mregDC and Tfh-like niches enable local reinvigoration of CD8 T cells following PD-1 blockade

Project description:While T cell accumulation in tumors is associated with response to immune checkpoint blockade (ICB), many T cell-rich tumors fail to respond to ICB. Here we leveraged a large neoadjuvant PD-1 blockade trial in hepatocellular carcinoma (HCC) to search for correlates of ICB response within T cell-rich tumors. Paired scRNAseq/TCRseq of nearly one million immune cells revealed that tumor responses to ICB correlated with significant clonal expansion of intratumoral CH25H+CXCL13+IL-21+CD4 T cells and GranzymeK+PD-1+CD8 effector T cells, whereas terminally exhausted CD39hiToxhiPD-1hi CD8 clones dominated in non-responders. Notably, proliferating and progenitor CD8 T cells clones were found in tumors of responders and non-responders. However, tumors from responders were highly enriched in mregDCs, a DC state triggered by capture of tumor debris, which formed physically interacting cellular triads with Tfh-like CD4 and progenitor-like CD8 T cells. Receptor-ligand analysis revealed unique interactions within these triads that may promote progenitor CD8 T cell differentiation into effector cells upon PD-1 blockade. These results suggest that discrete cellular niches that include mregDCs and Tfh-like CD4 T cells might control the differentiation of tumor-specific progenitor CD8 T cell clones into effective anti-tumor T cells in human tumors.

2023-06-16 | GSE206325 | GEO

Cytotoxic NK cells impede response to checkpoint immunotherapy in melanoma with an immune-excluded phenotype

Project description:The inability of lymphocytes to infiltrate the tumor nest drastically limits immune checkpoint blockade (ICB) responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of melanoma patients undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from non-responders. Spatial OMICs revealed that while NK cells colocalized with CD8 T cells within the tumor bed in responding lesions, they were excluded from the tumor parenchyma in non-responding lesions. Strikingly, depletion of NK cells using a NK1.1 antibody or the FDA-approved drug Daratumumab in a unique melanoma mouse model exhibiting an immune-excluded phenotype unleashed immune infiltration of the tumor core and tumor clearance upon ICB exposure. Mechanistically, we show that NK cells are actively recruited to immune-excluded areas upon ICB exposure via the chemokine receptor CX3CR1 to suppress tumor infiltration and antitumor function of CD8 T cells, possibly by promoting ferroptosis.

2025-05-28 | GSE292854 | GEO

tRF-22 RNA pulldown and Co-IP followed by LC-MS/MS in human cell samples

Project description:tRNA-derived fragments (tRFs) play a crucial role in tumor progression. However, whether and how tRFs regulate the immune response in esophageal squamous cell carcinoma (ESCC) and their potential clinical applications remain unclear. tRF-22 enhances myeloid-derived suppressor cells (MDSCs) infiltration via a tRF-22–hnRNPAB–TGFβ2 axis, which in turn leads to the suppression of CD8+ T cells. Targeting tRF-22 or TGFβ2 reactivates antitumor immunity and synergistically enhances the effectiveness of anti-PD1 therapy in ESCC. Patients with lower tRF-22 levels exhibit better responses to immunotherapy and longer progression-free survival in our ESCC-ICB cohort.

2026-01-12 | PXD057698 | Pride

Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

2023-06-16 | MSV000092193 | MassIVE

Blood immunomap for prediction of responses to anti-PD-1 immunotherapy in metastatic non-small cell lung cancer

Project description:The identification of circulating predictors of response to ICB therapy is vital as very few of them meet the demands of the clinic. Herein, by using high-dimensionality mass cytometry, we designed a blood immunomap in metastatic NSCLC individuals who underwent anti-PD-1 treatment. We identified heightened frequencies of CD8+PD-L1+ T cells in non-responders compared responders. Notably, Imaging Mass Cytometry data revealed that CD8+PD-L1+ T cells were enriched in tumor biopsies, pleural infusions and BAL of early-stage NSCLC individuals, proposing this cells subset as candidate not only for the advanced but also for early disease detection. Transcriptomic analysis unveiled that CD8+PD-L1+ T cells displayed an exhausted phenotype related to their increased frequencies to non-responders to immunotherapy, and gene signatures correlated with the overall survival of an independent cohort. Overall, our study pinpoints immune-related events which may benefit the quest for detection of predictive biomarkers of immunotherapy responses.

2025-05-31 | GSE295969 | GEO

The CX3CL1-CX3CR1 chemokine axis can contribute to tumor immune evasion and blockade with a novel CX3CR1 monoclonal antibody enhances responses to anti-PD-1 immunotherapy [CT26]

Project description:To investigate the imunoresistance programs regulated by the CX3CL1-CX3CR1 axis, we treated CT26 mouse tumor cell line with CX3CL1, CX3CL1 + IFN-γ, IFN-γ, and no treatment

2023-09-01 | GSE215269 | GEO

CX3CL1 and IL-15 Promote CD8 T Cell Chemoattraction in HIV and in Atherosclerosis

Project description:Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated 60 CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.

2020-10-12 | GSE154644 | 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

Dual Relief of T-Lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Project description:Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.

2020-05-01 | GSE148162 | GEO

Checkpoint blockade induced CD8+ T cell differentiation in responders in head and neck cancers

Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.

2021-12-01 | GSE153383 | 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