Human effector CD8+ T cells with an activated and exhausted-like phenotype control tumour growth in vivo in a humanized tumour model
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ABSTRACT:
PROVIDER: PRJEB75430 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13030752.fastq.gz | Fastqsanger.gz | |||
| ERR13030753.fastq.gz | Fastqsanger.gz | |||
| ERR13030754.fastq.gz | Fastqsanger.gz | |||
| ERR13030755.fastq.gz | Fastqsanger.gz | |||
| ERR13030756.fastq.gz | Fastqsanger.gz |
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Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress
Project description:BackgroundHumanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.MethodsWe established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.FindingsWe found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), terminally exhausted (Tex-term) and tissue-resident (TRM) cells in tumour-bearing humanized mice with accumulation of Tex-term and TRM in the tumour. In addition, we identified tumour-reactive CD8+ T cells through expression of CD137. This subpopulation of de novo arising human CD137+ CD8+ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137+ CD8+ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8+ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8+ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137+ CD8+ T cells showed reduced tumour growth and higher CD8+ T cell tumour infiltration, correlating with control of human tumours.InterpretationWe established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8+ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.FundingSwiss Cancer Research foundation.
| S-EPMC11296066 | biostudies-literature
Project description:Terminally exhausted CD8+ T-cells, which hold certain level of anti-tumour cytotoxicity but largely reduced proliferation capacity, contribute directly to tumour growth control. However, this subpopulation do not respond to immune checkpoint blockades or most existing immunotherapies and are difficult to be reactivated. Here, we show that a half-life extended interleukin (IL)-10/Fc fusion protein directly expands the terminally exhausted CD8+ TILs and sustains their effector functions through in vivo metabolic reprogramming, leading to eradication of established solid tumours and durable cures in a majority of treated mice when combined with adoptive T-cell transfer immunotherapy. Our results provide preclinical evidence that IL-10/Fc is a safe and highly effective therapy that acts on a specific subset of CD8+ TILs distinct from those responding to immune checkpoint blockades. Thus, IL-10/Fc could complement and synergize with existing cancer immunotherapies for enhanced efficacy and response rates. We find that IL-10/Fc reprograms T-cell metabolism by promoting oxidative phosphorylation through the mitochondrial pyruvate carrier, suggesting that metabolic reprogramming is sufficient to revitalize terminally exhausted CD8+ TILs.
2021-04-01 | GSE168990 | GEO
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Keywords: infection response
2007-11-27 | GSE9650 | GEO
Project description:Since exhausted CD8 T-cells are known to have a strong epigenetic imprint, which is a major obstacle for reinvigoration, we investigated whether the induced Klf4 expression could change the epigenetic status of the exhausted CD8 T-cells. For this, we performed ATAC-sequencing and compared chromatin landscapes between naïve, in vitro generated effector, exhausted (GFP-induced), and reinvigorated (KLF4-induced) CD8 T-cells.
2022-10-24 | GSE212805 | GEO
Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.
2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress
Project description:Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy. RNA expression was measured by RNA-Seq on day 5 of cultures, maintained in individual biologial triplicates which were stimulated with immobilized anti-CD3/28 antibodies or kept in complete media (no stim) - with equivalent conditions treated with isotonic media containing elevated potassium.
2016-08-13 | E-GEOD-84996 | biostudies-arrayexpress
Project description:The differential expression of metabolic genes between effector and exhausted CD8+ Tcells has been characterized in the people living with HIV (PLWH) using 768 genes from the NanoString Human Metabolic Pathways Panel.
2024-07-01 | GSE270720 | GEO
Project description:Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy.
2016-08-13 | GSE84996 | GEO
Project description:Tissue-resident memory T cells (Trm) play a central role in regional immunity within non lymphoid tissues to efficiently protect against reinfection as well as to control persistent pathogen infection. Although single-cell transcriptomics analysis of Trm in various diseases have uncovered a phenotypic and functional heterogeneity of Trm, the underlying molecular mechanisms directing such diversity are poorly defined. To better understand these mechanisms, we used the model of infection with the parasite Toxoplasma gondii (T. gondii), which establishes a persistent infection in the central nervous system (CNS) controlled by brain CD8+ Trm. Through single-cell transcriptomic analysis of brain CD8+ T cells from T.gondii-infected mice, we uncovered that brain Trm subsets have an heterogenous expression of the transcriptional regulator Id2, and that these differences in Id2 levels correlated with different functional states. Using mixed bone marrow chimeras, our results revealed that T-cell specific Id2-deficiency caused parasite-specific Trm to develop an aberrant phenotype in a cell-intrinsic manner, characterized by diminished effector functions and reduced expression of the tissue retention molecules CD49a and CXCR6. This phenotype was similarly observed upon overexpression of E2A, a transcription factor negatively regulated by Id2, in parasite-specific CD8+ T cells. Conversely, the loss of Id2 in brain-infiltrating CD8+ T cells led to the accumulation of exhausted PD1+ Tox+ CD8+ Trm cells, whereas Id2 overexpression repressed the acquisition of the exhaustion phenotype and promoted the accumulation of pathogen-specific CD8+ T cells in the brain. Overall, our study indicates that Id2 expression level dictates the acquisition of an effector vs. exhausted phenotype by CD8+ Trm during chronic CNS pathogen infection.
2025-05-22 | GSE270492 | GEO